Discovery and optimization of a novel series of highly CNS penetrant M₄ PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core

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• 作者：Michael R. Wood^a ; ^c ; ^&dagger ; ; Meredith J. Noetzel^a ; ^b ; ^&dagger ; ; Julie L. Engers^a ; Katrina A. Bollinger^a ; Bruce J. Melancon^a ; ^b ; James C. Tarr^a ; Changho Han^a ; Mary West^a ; Alison R. Gregro^a ; Atin Lamsal^a ; Sichen Chang^a ; Sonia Ajmera^a ; Emery Smith^d ; Peter Chase^d ; Peter S. Hodder^e ; Michael Bubser^a ; Carrie K. Jones^a ; ^b ; ^g ; Corey R. Hopkins^a ; ^b ; ^c ; Kyle A. Emmitte^a ; ^b ; ^c ; Colleen M. Niswender^a ; ^b ; ^g ; Michael W. Wood^f ; Mark E. Duggan^f ; P. Jeffrey Conn^a ; ^b ; ^g ; Thomas M. Bridges^a ; ^b ; ^{thomas.m.bridges@vanderbilt.edu" class="auth_mail" title="E-mail the corresponding author} ; Craig W. Lindsley^a ; ^b ; ^c ; ^{craig.lindsley@vanderbilt.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：M4 ; Muscarinic acetylcholine receptor ; Positive allosteric modulator (PAM) ; Schizophrenia ; Structure&ndash ; Activity Relationship (SAR)
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：26
• 期：13
• 页码：3029-3033
• 全文大小：2502 K

文摘

This Letter describes the chemical optimization of a novel series of M₄ positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma K_p = 0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M₄ PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma K_p > 10). Moreover, this campaign provided fundamentally distinct M₄ PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.