☆ 4.5 Article

Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2012)

期刊

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷 22, 期 15, 页码 5084-5088

出版社

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.bmcl.2012.05.109

关键词

Positive allosteric modulator; M-4; ML293; CNS penetration; Muscarinic receptor 4

类别

Chemistry, Medicinal Chemistry, Organic

资金

NIMH NIH HHS [U19 MH097056, U01 MH087965, U54MH084659, R01 MH073676, U54 MH084659] Funding Source: Medline

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摘要

Herein we describe the discovery and development of a novel class of M-4 positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC50 = 1.3 mu M) and excellent efficacy as noted by the 14.6-fold leftward shift of the agonist concentration-response curve. ML293 was also selective versus the other muscarinic subtypes and displayed excellent in vivo PK properties in rat with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1 h, [Brain] = 10.3 mu M, B: P = 0.85). (C) 2012 Elsevier Ltd. All rights reserved.

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