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

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 15; pp. 5084 - 5088
• Main Authors: 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., Scott Daniels, J., Jeffrey Conn, P., Niswender, Colleen M., Lindsley, Craig W., Hopkins, Corey R.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2012; Elsevier
• Subjects: Allosteric Regulation; Amides - chemistry; Animals; Biological and medical sciences; Brain - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CHO Cells; CNS penetration; Cricetinae; Cricetulus; Drug Evaluation, Preclinical; Humans; Life Sciences & Biomedicine; Medical sciences; ML293; Muscarinic receptor 4; Niacinamide - analogs & derivatives; Niacinamide - chemistry; Niacinamide - pharmacokinetics; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Positive allosteric modulator; Rats; Receptor, Muscarinic M4 - chemistry; Receptor, Muscarinic M4 - metabolism; Science & Technology; Structure-Activity Relationship; Positive allosteric modulator; Muscarinic receptor 4; ML293; CNS penetration; M4; ACETYLCHOLINE-RECEPTORS; M-4; CENTRAL-NERVOUS-SYSTEM; KNOCKOUT MICE; Thiazole derivatives; Selectivity; Blood brain barrier; M; Cholinergic receptor; Allosteric regulation; Muscarinic receptor; M4 muscarinic receptor; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.109

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=1.3μM) 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 (11.6mL/min/kg) and excellent brain exposure (PO PBL, 10mg/kg at 1h, [Brain]=10.3μM, B:P=0.85).