Discovery of Orally Bioavailable 1,3,4-Trisubstituted 2-Oxopiperazine-Based Melanocortin-4 Receptor Agonists as Potential Antiobesity Agents.
作者
Tian, Xinrong;Switzer, Adrian G.;Derose, Steve A.;Mishra, Rajesh K.;Solinsky, Mark G.;Mumin, Rashid N.;Ebetino, Frank H.;Jayasinghe, Lalith R.;Webster, Mark E.;Colson, Anny-Odile;Crossdoersen, Doreen;Pinney, Beth B.;Farmer, Julie A.;Dowty, Martin E.;Obrin
[摘要]：basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Pr analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-Pr analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compd. 35 showed promising oral bioavailability and a moderate oral half life and induced significant wt. loss in a 28-day rat obesity model.
