Lead optimization of the VU0486321 series of mGlu₁ PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool

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• 作者：Pedro M. Garcia-Barrantes^a ; Hyekyung P. Cho^a ; ^b ; Adam M. Metts^c ; Anna L. Blobaum^a ; Colleen M. Niswender^a ; ^b ; P. Jeffrey Conn^a ; ^b ; Craig W. Lindsley^a ; ^b ; ^c ; ^{craig.lindsley@vanderbilt.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：mGlu1 ; Metabotropic glutamate 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 February 2016
• 年：2016
• 卷：26
• 期：3
• 页码：751-756
• 全文大小：3275 K

文摘

This Letter describes the further lead optimization of the VU0486321 series of mGlu₁ positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu₁ PAMs (EC₅₀s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest F_u) and CNS penetration (K_ps 0.25–0.97), along with up to >450-fold selectivity versus mGlu₄ and mGlu₅.