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

Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.33). 06/2012; 22(15):5084-8. DOI: 10.1016/j.bmcl.2012.05.109
Source: PubMed

ABSTRACT 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).