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.

Salovich JM, Vinson PN, Sheffler DJ, Lamsal A, Utley TJ, Blobaum AL, Bridges TM, Le U, Jones CK, Wood MR, Daniels JS, Conn PJ, Niswender CM, Lindsley CW, Hopkins CR
Bioorg Med Chem Lett. 2012 22 (15): 5084-8

PMID: 22738637 · PMCID: PMC3401285 · DOI:10.1016/j.bmcl.2012.05.109

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 (EC(50)=1.3 μM) 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 1h, [Brain]=10.3 μM, B:P=0.85).

Copyright © 2012 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

Allosteric Regulation Amides Animals Brain CHO Cells Cricetinae Cricetulus Drug Evaluation, Preclinical Humans Niacinamide Rats Receptor, Muscarinic M4 Structure-Activity Relationship

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