Open AccessDiscovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput “Unbiased” Screening Campaign
Author(s) -
Skye R. Doering,
Katie T. Freeman,
Ginamarie Debevec,
Phaedra Geer,
Radleigh G. Santos,
Travis LaVoi,
Marc Giulianotti,
Clemencia Pinilla,
Jon R. Appel,
Richard A. Houghten,
Mark D. Ericson,
Carrie HaskellLuevano
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c02041
Subject(s) - chemistry , guanidine , pyrrolidine , agonist , melanocortin , melanocortin 4 receptor , small molecule , drug discovery , receptor , pharmacology , stereochemistry , combinatorial chemistry , biochemistry , medicine
The central melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are key regulators of body weight and energy homeostasis. Herein, the discovery and characterization of first-in-class small molecule melanocortin agonists with selectivity for the melanocortin-3 receptor over the melanocortin-4 receptor are reported. Identified via "unbiased" mixture-based high-throughput screening approaches, pharmacological evaluation of these pyrrolidine bis-cyclic guanidines resulted in nanomolar agonist activity at the melanocortin-3 receptor. The pharmacological profiles at the remaining melanocortin receptor subtypes tested indicated similar agonist potencies at both the melanocortin-1 and melanocortin-5 receptors and antagonist or micromolar agonist activities at the melanocortin-4 receptor. This group of small molecules represents a new area of chemical space for the melanocortin receptors with mixed receptor pharmacology profiles that may serve as novel lead compounds to modulate states of dysregulated energy balance.