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.
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).
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
James M
JM
Salovich
Paige N
PN
Vinson
Douglas J
DJ
Sheffler
Atin
A
Lamsal
Thomas J
TJ
Utley
Anna L
AL
Blobaum
Thomas M
TM
Bridges
Uyen
U
Le
Carrie K
CK
Jones
Michael R
MR
Wood
J Scott
JS
Daniels
P Jeffrey
PJ
Conn
Colleen M
CM
Niswender
Craig W
CW
Lindsley
Corey R
CR
Hopkins
D000494:Allosteric Regulation; D000577:Amides / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; C576338:N-(4-methoxy-7-methylbenzo(d)thiazol-2-yl)isonicatinamide; D043588:Receptor, Muscarinic M4; D009536:Niacinamide