Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Design, Synthesis, and Structure–Activity Relationships Study of N-Pyrimidyl/Pyridyl-2-thiazolamine Analogues as Novel Positive Allosteric Modulators of M3 Muscarinic Acetylcholine Receptor
Hiroaki TanakaMichinori AkaiwaKenji NegoroEiji KawaminamiHisashi MiharaHideyoshi FujiRisa OkimotoKatsutoshi InoKenichiro IshizuTaisuke Takahashi
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2021 Volume 69 Issue 4 Pages 360-373


The M3 muscarinic acetylcholine receptor (mAChR) plays an essential pharmacological role in mediating a broad range of actions of acetylcholine (ACh) released throughout the periphery and central nerve system (CNS). Nevertheless, its agonistic functions remain unclear due to the lack of available subtype-selective agonists or positive allosteric modulators (PAMs). In the course of our extended structure–activity relationships (SARs) study on 2-acylaminothiazole derivative 1, a previously reported PAM of the M3 mAChR, we successfully identified N-pyrimidyl/pyridyl-2-thiazolamine analogues as new scaffolds. The SARs study was rationalized using conformational analyses based on intramolecular interactions. A comprehensive study of a series of analogues described in this paper suggests that a unique sulfur–nitrogen nonbonding interaction in the N-pyrimidyl/pyridyl-2-thiazolamine moiety enable conformations that are essential for activity. Further, a SARs study around the N-pyrimidyl/pyridyl-2-thiazolamine core culminated in the discovery of compound 3g, which showed potent in vitro PAM activity for the M3 mAChR with excellent subtype selectivity. Compound 3g also showed a distinct pharmacological effect on isolated smooth muscle tissue from rat bladder and favorable pharmacokinetics profiles, suggesting its potential as a chemical tool for probing the M3 mAChR in further research.

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