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

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• 作者：James M. Salovich ; Paige N. Vinson ; Douglas J. Sheffler ; Atin Lamsal ; Thomas J. Utley ; Anna L. Blobaum ; Thomas M. Bridges ; Uyen Le ; Carrie K. Jones ; Michael R. Wood ; J. Scott Daniels ; P. Jeffrey Conn ; Colleen M. Niswender ; Craig W. Lindsley ; Corey R. Hopkins
• 关键词：Positive allosteric modulator ; M4 ; ML293 ; CNS penetration ; Muscarinic receptor 4
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 August, 2012
• 年：2012
• 卷：22
• 期：15
• 页码：5084-5088
• 全文大小：4383 K

文摘

Herein we describe the discovery and development of a novel class of M₄ positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC₅₀ = 1.3 ¦ÌM) 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 ¦ÌM, B:P = 0.85).