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.

Autor:	Davoren JE, Lee CW, Garnsey M, Brodney MA, Cordes J, Dlugolenski K, Edgerton JR, Harris AR, Helal CJ, Jenkinson S; Drug Safety Research and Development, Pfizer Worldwide Research and Development , La Jolla, California 92121, United States., Kauffman GW, Kenakin TP; Department of Pharmacology, University of North Carolina School of Medicine , Chapel Hill, North Carolina 27599, United States., Lazzaro JT, Lotarski SM, Mao Y, Nason DM, Northcott C, Nottebaum L; Drug Safety Research and Development, Pfizer Worldwide Research and Development , La Jolla, California 92121, United States., O'Neil SV, Pettersen B, Popiolek M, Reinhart V, Salomon-Ferrer R, Steyn SJ, Webb D, Zhang L, Grimwood S
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 Jul 14; Vol. 59 (13), pp. 6313-28. Date of Electronic Publication: 2016 Jul 01.
DOI:	10.1021/acs.jmedchem.6b00544
Abstrakt:	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.
Databáze:	MEDLINE
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