Article

Synthesis and characterization of pyrrolidine derivatives as potent agonists of the human melanocortin-4 receptor.

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Bioorganic & medicinal chemistry letters (impact factor: 2.65). 01/2008; 17(23):6546-52. DOI:10.1016/j.bmcl.2007.09.079 pp.6546-52
Source: PubMed

ABSTRACT A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats.

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Keywords

antagonist activity
 
diastereoisomers 20f-1
 
diet-induced obese rats
 
human melanocortin-4 receptor
 
Interestingly
 
MC4R agonist 20f-1
 
melanocortin receptor subtypes
 
potent functional agonist