Heterobiaryl and heterobiaryl ether derived M5 positive allosteric modulators.
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative parallel synthesis approach was employed to incorporate basic heterocycles to improve physiochemical properties.
Bridges
Thomas M
TM
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Kennedy
J Phillip
JP
Hopkins
Corey R
CR
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D006801:Humans; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D004987:Ethers; D006571:Heterocyclic Compounds; D011976:Receptors, Muscarinic
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