Discovery of a Novel 2,3-Dimethylimidazo[1,2-a]pyrazine-6-carboxamide M4 Positive Allosteric Modulator (PAM) Chemotype.

Kayla J. Temple, Julie L. Engers,Madeline F. Long,Katherine J. Watson,Sichen Chang,Vincent B. Luscombe,Matthew T. Jenkins, Alice L. Rodriguez,Colleen M. Niswender, Thomas M. Bridges,P. Jeffrey Conn,Darren W. Engers,Craig W. Lindsley

Bioorganic &amp Medicinal Chemistry Letters（2020）

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摘要

This Letter details our efforts to discover structurally unique M4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide core that provided improved M4 PAM activity and CNS penetration.

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关键词

M-4,Muscarinic acetylcholine receptor,Positive allosteric modulator (PAM),Structure activity relationship (SAR)

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