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 (M-4) receptor

作者：Salovich James M; Vinson Paige N; Sheffler Douglas J; Lamsal Atin; Utley Thomas J; Blobaum Anna L; Bridges Thomas M; Le Uyen; Jones Carrie K; Wood Michael R; Daniels J Scott; Conn P Jeffrey; Niswender Colleen M; Lindsley Craig W; Hopkins Corey R^*

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(15): 5084-5088.

DOI：10.1016/j.bmcl.2012.05.109

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

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).

• 出版日期2012-8-1