Udenafil Erectile Dysfunction [111115

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Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular Weight

South Korea

Dong-A South Korea

Dong-A Zydena 268203-93-6 516.66

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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 antagonist of human PDE5 with an IC50 of 8.25 nM and a comparable selectivity profile as sildenafil for the other PDEs. Unlike ta-dalafil, it does not inhibit PDE11, which has been implicated in myalgia and testicular toxicity. The key steps in the synthesis of udenafil involve the coupling of

1-methyl-3-propyl-4-amino-5-carbamoyl pyrazole with 2-propoxybenzoyl chloride, chlorosulfonation of the resulting product, reaction of the sulfonyl chloride with

2-(2-aminoethyl)-1-methylpyrrolidine, and finally ring closure to build the pyri-midinone ring of the core. In Phase I studies to assess the safety, tolerability, and pharmacokinetics of udenafil, single doses of 12.5-400 mg and multiple doses of 100 and 200mg/day were well-tolerated, and exposure increased in a dose-dependent manner. While the absolute oral bioavailability has not been determined in humans, it is absorbed rapidly; the oral bioavailability for multiple animal species averaged about 30%. With a Tmax of 1 - 1.5 h and a terminal half-life of 11 - 13h, udenafil has a rapid onset with a long duration of action. While udenafil is biotransformed to three major metabolites by rat microsomes, the predominant active metabolite in humans is the N-dealkylated sulfonamide, generated via CYP3A4 metabolism. Coadministration with strong CYP3A4 inhibitors or inducers could, therefore, alter the metabolism of udenafil and significantly change the pharmacokinetics. In vitro studies in pooled human liver microsomes demonstrated that the selective CYP3A4 inhibitor ketoconazole effectively inhibited the N-dealkylation of udenafil. To assess efficacy, a randomized, double-blind, placebo-controlled, fixed-dose Phase II trial was conducted in 319 ED patients. The change in the International Index of Erectile Function (IIEF) score from baseline to the end of the 12-week study was used as the primary efficacy endpoint. After 12 weeks of therapy, the udenafil-treated group, receiving either 100 or 200 mg, had significantly higher IIEF scores than the placebo group. Furthermore, udenafil produced up to a 91% vaginal penetration success rate and up to a 67% intercourse completion rate compared to a 29% completion rate by placebo. Overall patient satisfaction, measured by a standard global assessment question, was 86% compared to only 26% in the placebo group. The most frequently recorded adverse events were mild-to-moderate facial flushing and headache.

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