Quinolones

Moxifloxacin, 4, is a methoxyfluoroquinolone which is already available and approved for the treatment of acute respiratory infections such as community-acquired pneumonia, intra-abdominal infections, acute sinusitis, and skin infections. It is an inhibitor of DNA gyrase, which is an enzyme important in bacterial growth and replication. It has an excellent safety profile and has already been used by 42 million patients worldwide. However, the drug has not been adequately evaluated in children...

The reninangiotensin system

In the classical rennin-angiotensin system (RAS), renin is synthesized in juxtaglomerular cells of the kidney in response to various signals and is secreted into the blood. Renin cleaves the protein angiotensinogen, produced primarily in the liver, liberating the physiologically inert decapeptide angiotensin I (Ang I). Ang I is further cleaved by ACE to the octapeptide angiotensin II (Ang II), which activates the Ang II type 1 receptor (ATi). One of the downstream effects of ATi activation is a...

SSRI a2 antagonism

A2 adrenergic receptors act as autoreceptors for NE neurons in much the same way that 5-HT1 receptors regulate serotonergic neurons. Thus, antagonism of a2 receptors would prevent the negative feedback NE exerts on its own synthesis, neuronal firing, and release 26 . a2 antagonism also results in increased extracellular dopamine, acetylcholine, and 5-HT levels in vivo in rats and humans 27 . It has therefore been proposed that a combination of SERT inhibition and a2 antagonism could result in...

Conclusion

Clearly there is a large amount of research being done in the search for new antidepressants. Due to space limitations, this review has highlighted only some of the strategies being pursued. Other emerging areas of research include the modulation of glutamatergic neurotransmission 53 , GABA 54 , cytokines 55,56 , and neurotrophins 57 . While much research remains focused on direct modulation of monoaminergic systems, other strategies involve manipulation of separate biological systems that are...

Pegaptanib Agerelated Macular Degeneration [5664

Originator First introduction Introduced by Trade name CAS Registry No Molecular weight Eyetech Pfizer Macugen 222716-86-1 approx. 50 kD Pegaptanib is the first anti-angiogenic agent launched for the treatment of age-related macular degeneration (AMD). Wet, or neovascular, AMD is the leading cause of vision loss in the elderly vision loss is the consequence of choroidal ne-ovascularization, leading to leakage of blood or serum, retinal detachment, and fibrovascular scarring. The underlying...

Aryl acetic acid derivatives

4-Aryloxy phenylacetic acid derivatives, such as compound 49, have been reported as CRTH2 antagonists 81,82 . The activity of these compounds was evaluated in a 3H -PGD2 binding assay in HEK293 cells transfected with CRTH2. Compound 49 and several related analogs were reported to have IC50 values below 1 mM. Similarly, substituted 5-thiazole acetic acid derivatives, exemplified by 50, have been reported as CRTH2 antagonists 83 . This compound and its derivatives displayed IC50 values below 0.5...

Tigecycline Antibiotic [97103

The emergence of drug-resistant bacteria has diminished the clinical utility of the tetracyclines. Research to circumvent the efflux and ribosomal protection mechanisms of bacteria has led to the development of the glycylcyclines. Tigecycline is the first glycylcycline antibiotic to launch for the parenteral treatment of baterial infection, including complicated intra-abdominal and skin infections. Its mechanism of action involves inhibiting protein translation in bacteria by binding to the 30S...

Sordarins

Sordarins are a novel class of antifungal agents that act by selectively inhibiting the protein synthesis elongation step of fungi. They interact with translation elongation factor 2 of fungi and large ribosomal subunit stalk rpP0. This multiple mechanism may explain the high degree of selectivity of this class of compounds between fungal and mammalian cells 73 . Sordarins exhibit potent antifungal activities with relatively broad-spectrum activities in vitro and some compounds exhibit good...

Pramlintide Antidiabetic [6568

151126-32-8 (anhydrous free base) 196078-30-5 (acetate salt hydrate) 187887-46-3 (anhydrous acetate salt) 3949.4 (acetate salt) 4027.49 (acetate salt hydrate) Pramlintide is an injectable human amylin analog that has been launched for the treatment of both type 1 and type 2 diabetes, in conjunction with insulin. While it is also a 37-amino acid peptide, it differs from its parent predecessor by the substitution of Ala-25, Ser-28, and Ser-29 with prolines. Not only do these modifications improve...

Ciclesonide Asthma Copd [69

Trade name CAS registry no Molecular weight Altana Aventis Teijin Alvesco 126544-47-6 540.69 Ciclesonide, a new inhaled corticosteroid (ICS), is indicated for the prophylactic treatment of persistent asthma. ICS treatment is a widely accepted standard of care for maintenance therapy of chronic asthma, and the currently available agents include fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, and beclomethasone dipropionate. These agents exert their potent...

Serotonin 5HT6 antagonists

5-HT6 receptors are positively coupled to adenylyl cyclase 90 and are found in key brain regions associated with learning and memory including the olfactory tubercles, cerebral cortex, nucleus accumbens, striatum and hippocampus 91 . In addition, the atypical antipsychotics clozapine and olanzapine possess high affinity for the 5-HT6 receptor 92 . The potential of 5-HT6 antagonists in the treatment of cognitive disorders has been discussed in several recent reviews 93,94 , and the availability...

Darifenacin Urinary Incontinence [1518

Darifenacin demonstrates greater effect on tissues in which the predominant receptor type is M3 rather than Ml or M2. In vitro darifenacin inhibits carbachol-induced contractions with greater potency in isolated guinea-pig bladder (M3) than in guinea-pig atria (M2) or dog saphenous vein (Ml). In animal models, it shows greater selectivity for inhibition of detrusor contraction over salivation or tachycardia. The synthesis of darifenacin involves the coupling of 5-(2-bromoethyl)-2,...

Eszopiclone Hypnotic [3336

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight Eszopiclone is a non-benzodiazepine hypnotic agent indicated for the treatment of insomnia to induce sleep and for sleep maintenance. It has similar pharmacokinetic and pharmacodynamic parameters as the previously marketed non-benzodiazepine hypnotics zolpidem and zaleplon. However, unlike its predecessors, eszopiclone is not restricted to short-term treatment of insomnia. Clinical studies...

Fxr

FXR is a NHR acting as a physiological sensor for bile acids by controlling genes regulating their metabolism and transport 167-169 . The repression of key genes, Cyp7A1 and Cyp8B1 by FXR hold much of its promise as a therapeutic target. These encode for cholesterol 7a-hydroxlyase and sterol 12a-hydrolyase, which are enzymes central to the synthesis of bile acids from cholesterol 170,171 . Mice deficient in FXR are characterized by elevated serum TG, cholesterol and bile acids, increased...

Biological Target Validation

Over the past few years many reviews on the role of voltage-gated sodium channels in pain and overviews of biological target validation have been published 8-14 . In addition, human sodium channelopathies have been identified linking channels to pain states 15 . The roles of the various sodium channels in pain have been elucidated based on their biophysical properties, expression and localization or changes in expression in pain states, and the use of biological validation techniques such as...

Neuropeptide Y family modulators

NPY, PYY, PYY3_36, and PP are a class of polypeptide hormones that belong to the neuropeptide Y family. These peptides act through five receptor subtypes -NPY Y1-Y5 (Y6 subtype is found in mouse but not in primates or rats). Y1R is localized primarily in the brain and in the vasculature, while Y5R is found almost exclusively in the hypothalamus. Y2R is present in both the gastrointestinal tract and in the hypothalamus and is an autoreceptor, which negatively regulates NPY secretion. Y4R is...

Conclusion Of Medicinal Chemistry

The interest in the pharmaceutical industry to develop long-acting -adrenoceptor agonists with improved duration of action over salmeterol and formoterol is intense. The coming years will be pivotal as data for the most promising compounds will become available from clinical studies. There remains a continuing need for quality inhaled medicines for the treatment of asthma and COPD and it is a challenge to the industry to supply improved agents. 1 B. Waldeck, Eur. J. Pharmacol, 2002, 445, 1. 2...

Vasopressin

Arginine vasopressin (AVP) has been implicated in emotional behavior including depression and anxiety evidence was obtained initally through studies with nonselective V1a b receptor antagonists 51 . SSR149415, 32, was the first non-peptide selective V1b antagonist (K 1.54 nM) to be described 42 . Anxiolytic and antidepressant effects were demonstrated in animal models, including the chronic mild stress paradigm in mice 51,52 . In that model, increased neurogenesis was also demonstrated 43

Pyrimidines

5-Fucitosine (5-FC, 18) is a synthetic antifungal agent synthesized in 1957. In vivo it is converted into 5-fluorouracil (5-FU) within susceptible fungal cells, which is transformed into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA in place of uridylic acid. This alters the aminoacylation of tRNA, disturbs the amino acid pool and inhibits protein biosynthesis. A second mechanism of action is involved in the antifungal activity of 5-FC. 5-FU is metabolized into...

Quinolinones 8hydroxycarbostyril

Indacaterol, 3 (QAB-149) is currently being developed as a once daily b2-adrenoceptor agonist for the treatment of COPD and asthma 9 . Indacaterol contains the familiar quinolinone head group that appears in the marketed short-acting p2-adrenoceptor agonist, procaterol, 4. This 8-hydroxycarbostyril moiety is known to have a high affinity for the -adrenoceptor and has been postulated to give potential slow offset properties to ligands to drive duration of action 10 . A recently published patent...

Kur Kv15 and atrial arrhythmias

Atrial fibrillation is the most common tachyarrhythmia in man and affects nearly 4 of the population over 60 years of age and 9 of the population over 80 years of age 4,6,7 . In data derived from a diverse population it was estimated that 1 of all adults are diagnosed with atrial fibrillation 5 . When atrial fibrillation is persistent, drug therapy is often required. However, most of the currently available drugs were not designed to treat atrial arrhythmias and can have effects on other...

Serotonin 5HT2C receptor agonists

The serotonin (5-HT) receptor family are among the most studied of the neurotransmitters. The 5-HT2C receptor subclass has seen a great deal of research during the past 10 years, and evidence has established the potential as a target for treating anxiety, depression 107 , schizophrenia 108,109 and most notably obesity 110,111 . Until recently, attaining selectivity in the 5-HT2C receptor subclass over the closely related 5-HT2A and 5-HT2B receptors had been elusive, but selective agents are now...

Drugs targeting the RAS

Two prominent classes of antihypertensive drugs, the ACE inhibitors, e.g. benazepril, and the ARBs, e.g. valsartan, function by blocking the RAS. Despite the demonstrated efficacy of these drugs in controlling hypertension and reducing endorgan damage, both mechanisms of action have some disadvantages 10 . Complete inhibition of ACE does not prevent the conversion of Ang I to Ang II by other peptidases, including chymase. Indeed, in cardiac tissue, most Ang II is produced by enzymes other than...

Indole acetic acid derivatives and related compounds

Numerous 1-indole acetic acid derivatives compounds have been reported as CRTH2 antagonists. These include the tetrahydrocarbazole derivative 17, Rama-troban BAY U3405 , which is currently marketed in Japan for allergic rhinitis 51 . Ramatroban was developed as a thromboxane A2 receptor TP antagonist later it was also shown to be a CRTH2 antagonist. Ramatroban has been reported to reduce antigen-induced early and late-phase allergic responses in mice, rats and guinea pigs. In humans, Ramatroban...

Tipranavir Hiv [104110

Tipranavir, an oral non-peptidic HIV protease inhibitor, was granted accelerated approval for use in combination with ritanovir and was subsequently launched the same month in 2005. The targeted patient population includes HIV-1 infected adults with evidence of viral replication and demonstrated resistance to multiple protease inhibitors. As with other protease inhibitors, binding at the HIV-1 protease's active site inhibits the virus-specific processing of the Gag and Gag-Pol polyproteins in...

Prodrugs Of Poorly Soluble Compounds

Compounds are considered to be poorly soluble when their oral bioavailability is limited by the rate and extent of dissolution in the gastrointestinal GI tract. ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 41 ISSN 0065-7743 DOI 10.1016 S0065-7743 06 41027-7 2006 Elsevier Inc. All rights reserved A typical prodrug strategy in such cases focuses on chemical derivatization to improve water solubility. Highly polar, ionizable pro-moieties are often required to obtain an adequate level of...

Antioxidants

It was established in 1993 that activation of VCAM-1 expression on endothelial cells is partly regulated by a redox signal transduction pathway that is sensitive to inhibition by antioxidants. Pyrrolidine dithiocarbamate PDTC , a known antioxidant, at 50 mM inhibited over 90 of IL-1p-induced VCAM-1 expression in cultured human umbilical vein endothelial cells HUVEC 47,48 . These findings led to the search for new compounds with antioxidant properties as inhibitors of VCAM-1 expression. Probucol...

Possession Of Facts

There are two major categories of facts that form a basis for medicinal chemist's choices Table 1 . One is related to our understanding of how the human body, an extremely complex system, operates at all levels - molecular, cellular, organ and whole organism. The other has to do with our ability to know precisely what chemical compounds actually do in the body. Concerning the former, in spite of accumulating a significant body of information about it, we are very far from the complete...

Rasagiline Parkinsons Disease [7987

Country of origin Originator First introduction Introduced by Trade name CAS registry no mesylate salt 171.24 267.33 mesylate salt Rasagiline is a second-generation, irreversible monoamine oxidase type B MAO-B inhibitor that has been launched for the treatment of Parkinson's disease PD . Unlike its predecessor selegiline, it is not metabolized to amphetamine derivatives and is, therefore, devoid of the sympathomimetic activity responsible for adverse side effects. Rasagiline is, however,...

The Acyl Sulfonamide Antiproliferatives

In 2004, Lilly reported 8 the discovery and SAR of acylsulfonamide antiproliferative ASAP compounds of general structure 4. Subsequently, the activity of a second series 5 of thiophenyl acylsulfonamides was reported, and the compounds showed cellular activity comparable to the parent biaryl series Fig. 2 9 . The two initial leads 4a and 4b, one unsubstituted in the sulfonyl phenyl ring, and the other mono-substituted by chlorine in the ara-position of the same ring, were identified in...

Aminergic Receptor Modulators 41 5HT2CR agonists

The 5-HT2C receptor 5HT2CR was identified in 1986 and is widely expressed in the CNS 93 . Several lines of evidence support a role for this receptor in body weight regulation. KO mice exhibit a phenotype characterized by increased body weight relative to wild-type littermates average of 13 increase , increased food intake, and a significantly greater percentage of adipose tissue 48 increase 94 . The non-selective 5HT2CR agonist mCPP was found to reduce food intake in wild-type mice, but not in...

Introduction

In 2005, the FDA approved three new small molecules for cancer indications Fig. 1 nelarabine 1 Arranon , GlaxoSmithKline for acute lymphoblastic leukemia 1 , sorafenib 2 Nexavar , Bayer for advanced renal cell carcinoma 2 , and lenalido-mide 3 Revlimid , Celgene for treatment of patients with transfusion-dependent anemia due to myelodysplastic syndrome 3 . Each drug has a different mechanism of action MOA . Nelarabine is a prodrug of the antimetabolite ara-G, sorafenib inhibits several kinases,...

GHSR antagonists

Ghrelin is an octanoylated 28 amino acid peptide hormone that is synthesized principally in the oxyntic mucosal cells of the stomach. It binds to and activates the growth hormone secretagogue receptor GHSR ghrelin receptor which is expressed primarily but certainly not exclusively in the hypothalamus and the pituitary gland 54 . Intravenous administration of ghrelin has been reported to increase food intake in rodents and humans 55,56 . Plasma ghrelin levels rise pre-prandially and fall...

Sarscov 3clpro Inhibitors

Proteolytic processing of the coronavirus replicase polyproteins is essential for ongoing viral RNA synthesis. Therefore, the SARS-CoV proteases are attractive targets for the development of antiviral drugs to reduce viral replication and pathogenicity. The structure and activity of the coronavirus 3CLpro has already been elucidated and the design of inhibitors to 3CLpro as therapeutics has been proposed 9,10 . SARS-CoV 3CLpro has three domains I residues 8-101 , II residues 102-184 , and III...

Prodrugs With Other Benefits

Recent reports on inventive prodrug approaches targeting other benefits beyond improved oral bioavailability and selective tissue delivery are described in this section. Although sustained release of an active agent has hitherto been solely the subject of drug formulation studies, efforts toward prolonging plasma half-life using prodrugs have recently been reported. A polyserine-naltrexone conjugate 58, in a 10 1 ratio of serine to naltrexone , when administered to rats orally, afforded a...

Toxicophore In Trovafloxacin

Moiety in zafirlukast 1 to give the glutathione adduct 2 is a noteworthy extension to the SAR of the 3-methylindole activation pathway 30 . The thiophene fragment has similarly been associated with metabolic activation in a number of publications Table 2 however, there has been less evidence for activation of benzothiophene. A recent paper highlights metabolic activation of 2-substituted benzothiophenes 31 . Metabolism of the benzothiophene moiety in the 5-lipoxygenase inhibitor zileuton 3 has...

Miscellaneous

Recent patent applications have described novel chemical structures that do not fit into either of the above categories. Benzimidazoles e.g. 30 40 and quinazolines e.g. 31 have been claimed as GKAs 41 . The vital role of GK in glucose homeostasis has been established for some time. Developments over the last decade, including the discovery of the regulatory function of GKRP, identification of maturity-onset diabetes of the young MODY-2- , permanent neonatal diabetes PNDM- and Persistent...

Diamides blockers

Compound 8, IC50 0.15 mM against Nav1.7, was recently identified via HTS screening in a functional assay and has been extensively profiled 41,42 . It was nonselective when tested against Nav1.2, Nav1.5 and Nav1.7 in EP. This compound demonstrated both voltage- and use-dependence and blocked TTXr currents in dissociated mouse DRGs with an IC50 0.025 mM. It demonstrated activity in the rat formalin assay with either intradermal administration or i.v. administration. Poor PK properties oral...

Doripenem Antibiotic [2225

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight Doripenem is a parenteral carbapenem antibiotic launched last year in Japan for the treatment of bacterial respiratory and urinary tract infections. It is a 1p-methyl carbapenem derivative, and it is the fourth analog to be marketed in this series following the launch of meropenem, biapenem, and ertapenem in previous years. The introduction of a 1 p-methyl group to the carbapenem skeleton...

SARSCoV 3CLpro inhibitors from screening

Extensive screening has been carried out in an effort to find structural leads against SARS-CoV 3CLpro from existing drugs. A major advantage is that approved drugs with minimal modifications may have the possibility of gaining accelerated approval by US Food and Drug Administration. It was reported that Kaletra, a mixture of protease inhibitors - Lopinavir and Ritonavir, approved for treating HIV in 2000, shows some effectiveness against the SARS virus 30 . Based on this observation, the...

Indole acetic acid derivatives

4-Indole acetic acid derivatives as DP antagonists, exemplified by 8a, 8b and 8c, were derived from 3-indole acetic acids 35 . Compounds 8a, 8b and 8c demonstrated binding K values of 10, 13 and 33 nM, respectively, in 3H -PGD2 binding assays using mDP expressing CHO cell membranes. They also inhibited PGD2-induced cAMP formation in mDP expressing CHO cells in the presence of 0.1 BSA at IC50 values of 0.3, 0.43 and 0.57 mM, respectively 36 . Greater than 200fold selectivity was achieved with 8a...

Udenafil Erectile Dysfunction [111115

Introduction Introduced by Trade name CAS registry no Molecular Weight Udenafil is the fourth in a class of drugs targeting the inhibition of the enzyme phosphodiesterase 5 PDE5 for the treatment of erectile dysfunction. Inhibition of PDE5 results in the increase in endogenous cyclic guanosine monophosphate cGMP concentrations in the penile corpus cavernosum. cGMP induces smooth muscle cell relaxation and subsequent increased blood flow leading to a sustainable erection. Udenafil is a potent...

Azoles

Azole antifungal agents include imidazole and triazole derivatives that prevent the synthesis of ergosterol, a major component of fungal membranes, by inhibiting the cytochrome P-450-dependent enzyme 14a-lanosterol demethylase CYP51 10,11 . This enzyme contains an iron protoporphyrin unit located in its active site, which catalyzes the oxidative removal of the 14a-methyl group of lanosterol, by typical monooxygenase activity 12 . Azoles bind to the iron of the porphyrin 13 and cause the...

Sns595

SNS-595 6, SPC-595 formerly AG-7352 is a 1,8-disubstituted naphthyridine whose discovery and SAR were originally reported by Dainippon Pharmaceuticals 13,14 . The discovery came from screening antibacterial quinolines for antitumor activity, and finding that 1,8-naphthyridines possess cytotoxic activity against murine P388 leukemia. The rationale behind the screening for cytotoxic activity in tumors rather than bacteria was that the quinolone antibacterials are known to inhibit topoisomerase II...

Noncovalent SARSCoV 3CLpro inhibitors

Side effects and toxicity often arise with covalently bonded inhibitors which hinder or prevent their development as useful drug therapies 19,20 . To avoid such pitfalls, it is often desirable to design and develop non-covalent or reversible inhibitors as therapeutic agents. A series of synthetic small molecule, non-covalent inhibitors of SARS-CoV 3CLpro was published in 2004 21 . These investigators previously reported that keto-glutamine analogues with the phthalhydrazido group at a-position...

Selective PPARy modulators

In attempts to circumvent the previously described limitations of PPARg full agonists, zealous efforts are underway to identify and characterize selective PPARg modulators SPPARgMs or partial agonists that retain desirable efficacy and exhibit superior tolerability, an endeavor further complicated by the lack of a consistent definition for SPPARgMs and a precise understanding of the molecular mechanisms by which PPARg full agonists exert their deleterious effects. In principle, however, a...

Avian influenza vaccine

Traditionally, vaccination has been the principal approach to protecting individuals against influenza. Currently, no influenza A H5N1 vaccine is available although several candidate vaccines are being developed. Preliminary data suggest that either higher concentrations of antigens than used in seasonal influenza vaccines and or addition of adjuvants to these vaccines will be necessary to induce protective responses 8 . Gearing production, to rapidly make necessary quantities, of such a...

Future Outlook

It is with unprecedented rapidity that a basic understanding of SARS-CoV life cycle has been achieved. Already, a number of targets including SARS-CoV 3CLpro and SARS-CoV PLpro appear very promising for anti-SARS-CoV chemotherapy. Since the global outbreak of SARS ended in 2003, only a small number of cases of SARS associated with laboratory exposures have been reported. However, with the identification of Chinese horseshoe bats as an animal reservoir for SARS-CoV, the potential danger of the...

SSRI 5HT1D antagonism

The 5-HT1D receptor functions as an autoreceptor controlling the release of 5-HT from nerve terminals. Therefore a drug with a combination of SERT inhibition and 5-HT1D antagonism may also be of interest as a more rapid-acting antidepressant. Compound 12 was identified as a potent SSRI K 0.11 nM that also exhibits 5-HT1D affinity K 56 nM , with less affinity for the 5-HT1B receptor K 281 nM 25 . In microdialysis studies in guinea pigs 12 increased hypothalamic 5-HT levels as high as 300 of...

Other PPAR dual and pan agonists

Considerable effort has been expended to identify insulin sensitizers that retain useful activity on one or both of the other two PPAR isoforms. These include a series of PPARa 8 dual agonists i.e. 28 , though no in vivo data were provided 78 . The indole acetic acid 29 was a potent PPARa y 8 pan agonist with excellent efficacy in a rodent diabetes model 79,80 . A series of pan agonists with comparable receptor potencies were reported 30 showed significant activity in the db db model 81 ....

Ispinesib and related compounds

Clinical progress on ispinesib and SB-743921 Ispinesib SB-715992 CK0238273, 2 , one member of a KSP inhibitor series bearing a quinazolinone core, was the first mitotic kinesin inhibitor to enter clinical trials. Like its earlier reported analog 1, ispinesib was reported to be an allosteric inhibitor of KSP that binds at the motor domain and inhibits its ATPase activity in an ATP uncompetitive manner. It was also shown to be gt 70,000-fold selective for KSP versus other members of the...

LXR subtype selective agonists

The apparent liabilities of LXRa p dual agonists coupled with data garnered from LXR KO studies have led to a strong emphasis on the identification of LXR subtype selective agonists suitable for pharmacologic evaluation. Two natural products 57, 58 have been newly identified as LXRa-selective agonists with efficacy in cell-based assays IC50 a p 0.12 gt 15 and 1.3 50 mM, respectively 147 . Riccardin C 59 was identified as a LXRa agonist and a LXRp antagonist 148 unfortunately it exhibits weak...

Pyrroles

Sudoterb belongs to a class of compounds known as pyrroles, which are plant alkaloids. Sudoterb has been reported to have potent anti-TB activity in vitro and in vivo. In vitro, sudoterb has bactericidal activity similar to isoniazid and is synergistic with rifampin. The combination of sudoterb with isoniazid, rifampin, and pyrazinamide led to complete sterilization of both sensitive and MDR-TB strains in mice within two months, and in combination with rifampin and pyrazin-amide, cured TB in...

Subtype selective blockers

There have been a several reports of selective agents in the recent patent literature. In addition, in a press release Vertex has stated that they have entered into a deal with GSK to develop a selective Na channel blocker for neuropathic pain. Biarylpyridine derivatives 6 have been claimed to be at least 5-fold selective for Nav1.8 over the TTXs currents endogenously expressed in the SH-SY5Y neuroblastoma cell line 37 . Ambroxol 7, a secretolytic compound on the market for the treatment of...

Saligenins

The saligenin head group has been used with success to prepare long acting b2-adrenoceptor agonists with salmeterol playing a prominent role as a benchmark compound. In this connection, the combination agent AdvairTM salmeterol and fluticasone is currently in third place globally in terms of sales, demonstrating the success of this approach. A common tactic employed to initiate research in this area has been to emulate salmeterol and modify its scaffold to improve the duration of action of the...

Phenoxy acetic acid derivatives

Several research groups have independently reported on phenoxyacetic acid derivatives as antagonists of the CRTH2 receptor. Compound 53 exemplifies a family of 2-cycloalkyl phenoxyacetic acid antagonists of CRTH2 86 . This compound was reported to inhibit binding of 3H -PGD2 to the CRTH2 receptor in membranes from K562 or CHO cells with a K of 21 nM. In addition, compound 53 was reported to have an IC50 value of 139 nM in a cAMP assay using CHO cells expressing the CRTH2 receptor. Researchers...

SNRIs

Venlafaxine has become mainline therapy for major depressive disorder MDD and has been shown to have a higher remission rate than the SSRIs 11 . Duloxetine was launched in the U.S. in 2004 and is reported to have more balanced affinities at the serotonin transporter SERT and NET 12 . The next SNRI to be launched is likely to be desvenlafaxine 1 succinate, which is the succinate salt of an active metabolite of venlafaxine, and is currently undergoing FDA review. The SNRI F-98214-TA, 2, is a...

General themes

The generic pathways by which structural fragments may link to adverse outcomes are summarized in Fig. 1. Of particular note are idiosyncratic drug responses which Fig. 1. Pathways linking toxicophores to adverse outcome. Fig. 1. Pathways linking toxicophores to adverse outcome. often remain undetected until late stage clinical trials or post marketing when a large enough patient population is exposed to the drug to detect such a response. Such reactions are, by their very nature, difficult to...

Neuroprotection by polyADPribosepolymerase inhibitors

Poly ADP-ribose polymerase-1 PARP-1 is a chromatin-bound nuclear enzyme involved in a variety of physiological functions related to genomic repair, including DNA replication and repair, cellular proliferation and differentiation, and apoptosis 30 . PARP-1 functions as a DNA damage sensor and signaling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD , the nicotin-amide, and ADP-ribose and polymerizes the latter into nuclear acceptor proteins including histones, transcription...

PLpro Inhibitors

Numerous studies on the structural and mechanistic aspects of SARS-CoV 3CLpro have provided multiple avenues for structure-based design of antiviral compounds targeted against the 3CLpro active site 9,16,44,45 . On the other hand, structure-based design against the membrane-associated PLpro enzyme, either from SARS-CoV or related coronaviruses, has remained elusive due to lack of structural information. Unlike many coronaviruses that encode two PLpro paralogs PLP1 or PLP2 , SARS-CoV has a...

Small molecule antagonists

In the last decade there has been considerable interest in overcoming the shortcomings of the first generation peptide antagonists, by identifying orally active non-peptide oxytocin antagonists with a higher degree of selectivity towards the vaso-pressin receptors V1a, V1b, V2 . As a result, several templates have been investigated as potential selective oxytocin antagonists 8-10 . Reflecting the close structural similarity between the oxytocin and vasopressin receptors especially V1a, most of...

Prokinetic Agent Target Classes 21 Dopamine D2 receptor antagonists

Blockade of D2 receptors present on enteric neurons and or those located at the chemoreceptor trigger zone may promote motility. In fact, D2 receptor antagonists such as metoclopramide and domperidone are in use for the treatment of dyspeptic symptoms, despite potential side effects such as hyperprolactinemia and extrapyramidal dystonic reactions 1 . Itopride 1, which is available on the market in Japan, is a D2 receptor antagonist, which also exhibits acetylcholine esterase inhibition. The...

Luliconazole Antifungal [4547

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight Nihon Nohyaku Pola Lulicon 187164-19-8 354.28 Luliconazole is a member of the imidazole class of antifungal agents, with specific utility as a dermatological antimycotic drug. It was launched last year in Japan as a topical agent for the treatment of athlete's foot. Luliconazole is an optically active drug with R -configuration at its chiral center. It is structurally related to...

Exenatide Antidiabetic [3741

Exenatide is the first drug in a new class of anti-diabetics known as the incretin mimetics, and it is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, or both, but have not achieved adequate glycemic control. Exenatide is a functional analog of the human incretin Glucagon-Like Peptide-1 GLP-1 . GLP-1 is naturally released from cells in the GI tract in response to food intake and acts on its receptor on...

HT6R antagonists

The 5-HT6 receptor 5HT6R is expressed almost exclusively in the CNS. Several pharmacological studies and genetic models support a role for this receptor in obesity. 5HT6R KO mice were found to be resistant to body weight gain on a high fat diet 101 . Administration of 5HT6R antisense oligonucleotide complementary to bases 1-18 of the rat 5HT6R cDNA initiation sequence was shown to reduce both food intake and body weight of diet-induced obese rats over a 6-day period 102 . A brain penetrant...

SSRI 5HT1A antagonism

The dual SSRI-5-HT1A antagonist Lu 36-274 7, 5-HT1A K 4.5 nM, SERT IC50 6nM combines the 5-HT1A binding properties of a phenylpiperazine moiety with the SERT inhibitory ability of a 3-indolyl-alkylamine moiety 20 . Lu 36-275 is selective versus D2 dopaminergic receptors K 430 nM and to lesser degree versus a1 adrenoreceptors K 110 nM . Rat cortical 5-HT levels were increased to 500 of control after an acute dose of 16mg kg, sc. In the schedule-induced polydipsia SIP model Lu 36-274 reduced...

Oxytocin Antagonists and Agonists

GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK 2. Oxytocin antagonists 410 2.1. Peptide antagonists 411 2.2. Small molecule antagonists 412 3.2. Small molecule agonists 417 4. Conclusions 419 References 419

Strategic Directions

Overall, formation of reactive metabolites and subsequent covalent modification of macromolecules is a potential liability in drug discovery and a potential source of attrition. However, it must be emphasized that in most cases there is no conclusive evidence linking formation of reactive metabolites and idiosyncratic toxicity. Indeed, for some of the examples presented above alternative mechanisms have been proposed to explain the toxicity, which did not involve bioactivation. Nevertheless,...

Nuclear Hormone Receptor Modulators for the Treatment of Diabetes and Dyslipidemia

Wood and Jason W. Szewczyk Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA 2.4. PPARa y dual agonists 105 2.5. Other PPAR dual and pan agonists 107 2.6. Selective PPARy modulators 108 4.1. LXR subtype selective agonists 114 4.2. Current patent literature 115 6. Conclusion 118 References 118

Triple reuptake inhibitors

Triple reuptake inhibitors TRIs , which increase DA levels in addition to serotonin and NE, are expected to be as efficacious as monoamine oxidase inhibitors MAOIs without being limited by the same side effects and dietary restrictions that accompany MAOI use. The rationale for including DAT inhibition is partially based on the well-established role of dopaminergic systems in motivation and reward. Anhedonia and lack of interest, which are core symptoms of MDD, result from dopaminergic...

Alpha7 Nicotine acetylcholine receptor agonists and positive allosteric modulators

It is believed that neuronal nicotinic acetylcholine receptors nAChRs are involved in a variety of attention and cognitive processes 47 . These Ca2 permeable, ligand-gated ion channels modulate synaptic transmission in key regions of the CNS involved in learning and memory, including the hippocampus, thalamus and cerebral cortex 48-50 . Among the nAChRs, physiological, pharmacological and human genetic data suggest a link between the loss of a 7 nAChR and sensory gating deficits in...

Dopamine D1D5 receptor agonists

Many of the cognitive abnormalities in schizophrenia are similar to those resulting from damage to the prefrontal cortex PFC including attentional abnormalities, problems in reasoning and judgment and working memory deficits 69 . Together with evidence of reduced prefrontal dopaminergic function in schizophrenia, these observations have lead to the view that positive symptoms are due to subcortical hyperdopaminergia, while cognitive deficits are the results of hypodopaminergia in the PFC 70 ....

Emerging Mechanisms And Conclusions

Schizophrenia is the focus of intense preclinical and clinical research and is an area in which discoveries in the basic sciences are rapidly reviewed in the context of their potential therapeutic implications. Although it is not feasible to cover either the depth or breadth of the available subject matter in a review of this size, we will conclude with a brief mention of potential targets awaiting the development of the necessary biology and chemistry to establish their importance in this...

Novel Approaches for the Treatment of Schizophrenia

Schmidt Pfizer Global Research amp Development, Pfizer Inc., Eastern Point Road, Groton, CT, USA 2. Approaches targeting altered NMDA receptor function 4 2.3. Metabotropic glutamate receptors 7 3. Approaches primarily targeting cognition 10 3.1. Alpha7 Nicotine acetylcholine receptor agonists and positive allosteric modulators 10 3.2. Dopamine D1 D5 receptor agonists 11 3.3. Serotonin 5-HT6 antagonists 12 4. Approaches primarily targeting psychosis 13 4.1....

Metabotropic glutamate receptors

The metabotropic glutamate receptors are members of the G-protein coupled receptor family. There are eight metabotropic receptors grouped into three families. Group I receptors mGluR1 and 5 are linked to Gaq and increase phosphotidylinositol turnover to elevate intracellular Ca2 . Both groups II mGluR2 and 3 and III mGluR4, 6, 7 and 8 are negatively linked to adenylyl cyclase via Gai. Group II mGluRs are located presynaptically on glutamate terminals where they may act as autoreceptors...