期刊
CHEMICAL & PHARMACEUTICAL BULLETIN
卷 69, 期 4, 页码 360-373出版社
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/cpb.c20-00877
关键词
N-pyrimidyl-2-thiazolamine; N-pyridyl-2-thiazolamine; conformational analysis; intramolecular sulfur-nitrogen interaction; M-3 muscarinic acetylcholine receptor; positive allosteric modulator
In the study, N-pyrimidyl/pyridyl-2-thiazolamine analogues were identified as new scaffolds for the M-3 mAChR, showing unique sulfur-nitrogen nonbonding interactions essential for activity. Compound 3g was discovered to have potent in vitro PAM activity for the M-3 mAChR with excellent subtype selectivity and favorable pharmacokinetics profiles, suggesting its potential as a chemical tool for further research.
The M-3 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 M-3 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 M-3 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 M-3 mAChR in further research.
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