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Discovery, Optimization, and Biological Characterization of 2,3,6‐Trisubstituted Pyridine‐Containing M 4 Positive Allosteric Modulators
Author(s) -
Schubert Jeffrey W.,
Harrison Scott T.,
Mulhearn James,
Gomez Robert,
Tynebor Robert,
Jones Kristen,
Bunda Jaime,
Hanney Barbara,
Wai Jenny MiuChen,
Cox Chris,
McCauley John A.,
Sanders John M.,
Magliaro Brian,
O'Brien Julie,
Pajkovic Natasa,
Huszar Agrapides Sarah L.,
Taylor Anne,
Gotter Anthony,
Smith Sean M.,
Uslaner Jason,
Browne Susan,
Risso Stefania,
Egbertson Melissa
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900088
Subject(s) - allosteric regulation , chemistry , agonist , allosteric modulator , muscarinic acetylcholine receptor , potency , pharmacology , in vivo , knockout mouse , antagonist , receptor , stereochemistry , in vitro , biochemistry , biology , microbiology and biotechnology
Abstract Herein we describe the discovery and optimization of a new series of 2,3‐disubstituted and 2,3,6‐trisubstituted muscarinic acetylcholine receptor 4 (M 4 ) positive allosteric modulators (PAMs). Iterative libraries enabled rapid exploration of one‐dimensional structure–activity relationships (SAR) and identification of potency‐enhancing heterocycle and N ‐alkyl pyrazole substituents. Further optimization led to identification of the potent, receptor‐subtype‐selective, brain‐penetrant tool compound 24 (7‐[3‐[1‐[(1‐fluorocyclopentyl)methyl]pyrazol‐4‐yl]‐6‐methyl‐2‐pyridyl]‐3‐methoxycinnoline). It is efficacious in preclinical assays that are predictive of antipsychotic effects, producing dose‐dependent reversal of amphetamine‐induced hyperlocomotion in rats and mice, but not in M 4 knockout mice. Cholinergic‐related adverse effects observed in rats treated with 24 at unbound plasma concentrations more than 3‐fold higher than an efficacious dose in the hyperlocomotion assay were fewer and less severe than those observed in rats treated with the nonselective M 4 agonist xanomeline, suggesting a receptor‐subtype‐selective PAM has the potential for an improved safety profile.