Neuropeptide Receptor Modulators 31 MC4R agonists

The search for melanocortin-4 receptor (MC4R) agonist drugs continues to be a highly active area of research, with over 100 publications and patent applications appearing since the start of 2005. The biology of this area has recently been reviewed [29], and some of the rationale for this approach has been described in a recent journal issue dedicated to advances in melanocortin receptor pharmacology [30]. A review of small molecule melanocortin ligands (mainly focused on MC4R agonists) covering the literature to mid-2005 has also appeared recently [31]. Interesting biochemistry of the MC4R was reported in the past year suggesting that the receptor is constitutively active in vivo and that this is achieved by 'self-activation' from the N-terminus [32]. A model of the receptor-binding site derived using a combination of site-directed mutagenesis and molecular modeling has also appeared, which may provide guidance for agonist design [33].

The majority of MC4R patent applications and publications continue to be focused around two main structural classes - piperidyl amides derived from 4-halo-phenylalanine (class (1)), and piperidyl amides derived from 3,4-disubstituted pyrrolidines (class (2)). In class (1), compound 15 (RY764) appears to be the most advanced member to be publicly disclosed having been optimized for potency, selectivity for the MC4R, pharmacokinetic properties, and reduced formation of covalent protein adducts (a marker of toxicity) [34]. Discovery of this agent appears to have been prompted by problems encountered with the previously reported and structurally related agent 16 (MB243) [35,36]. Compound 15 was shown to be efficacious in rodent models of food intake.

Most of the work around class (2) agents has appeared in the patent application literature with limited detailed SAR. The genesis of this series has been described in a recent presentation [37]. Compound 17 is typical of examples from a recent application in which MC4R activity is claimed to be <10 mM [38].

Alternative small molecule MC4R agonist templates are starting to emerge in the patent application literature, for example the benzodiazepine 18 was shown to have a ^EC50 value of 7.22 in an MC4R functional screen [39].

Interestingly, while the majority of patent applications and publications appear to be focused toward small molecule MC4R agonists, peptidic agonists are still under active investigation. The cyclic derivative Ac-cyclo[hCys-His-(4Cl-D-Phe)-Arg-Trp-penicilla-mine]NH2 (19) was recently reported to have an MC4R K value of 0.03 nM [40].

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