Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects.
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.
Jennifer E
JE
Davoren
Che-Wah
CW
Lee
Michelle
M
Garnsey
Michael A
MA
Brodney
Jason
J
Cordes
Keith
K
Dlugolenski
Jeremy R
JR
Edgerton
Anthony R
AR
Harris
Christopher J
CJ
Helal
Drug Safety Research and Development, Pfizer Worldwide Research and Development , La Jolla, California 92121, United States.
Stephen
S
Jenkinson
Gregory W
GW
Kauffman
Department of Pharmacology, University of North Carolina School of Medicine , Chapel Hill, North Carolina 27599, United States.
Terrence P
TP
Kenakin
John T
JT
Lazzaro
Susan M
SM
Lotarski
Yuxia
Y
Mao
Deane M
DM
Nason
Carrie
C
Northcott
Drug Safety Research and Development, Pfizer Worldwide Research and Development , La Jolla, California 92121, United States.
Lisa
L
Nottebaum
Steven V
SV
O'Neil
Betty
B
Pettersen
Michael
M
Popiolek
Veronica
V
Reinhart
Romelia
R
Salomon-Ferrer
Stefanus J
SJ
Steyn
Damien
D
Webb
Lei
L
Zhang
Sarah
S
Grimwood
D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010848:Picolinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C000619497:N-(3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(1,3-thiazol-4-yl)benzyl)pyridine-2-carboxamide; D010848:Picolinic Acids; D043643:Receptor, Muscarinic M1; D013844:Thiazoles