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

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• 作者：Jennifer E. Davoren ; Che-Wah Lee ; Michelle Garnsey ; Michael A. Brodney ; Jason Cordes ; Keith Dlugolenski ; Jeremy R. Edgerton ; Anthony R. Harris ; Christopher J. Helal ; Stephen Jenkinson ; Gregory W. Kauffman ; Terrence P. Kenakin ; John T. Lazzaro ; Susan M. Lotarski ; Yuxia Mao ; Deane M. Nason ; Carrie Northcott ; Lisa Nottebaum ; Steven V. O’Neil ; Betty Pettersen ; Michael Popiolek ; Veronica Reinhart ; Romelia Salomon-Ferrer ; Stefanus J. Steyn ; Damien Webb ; Lei Zhang ; Sarah Grimwood
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6313-6328
• 全文大小：934K
• 年卷期：0
• ISSN：1520-4804

文摘

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.