Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

作者：Felts Andrew S; Rodriguez Alice L; Morrison Ryan D; Blobaum Anna L; Byers Frank W; Daniels J Scott; Niswender Colleen M; Conn P Jeffrey; Lindsley Craig W; Emmitte Kyle A^*

来源：Bioorganic & Medicinal Chemistry Letters, 2018, 28(10): 1679-1685.

DOI：10.1016/j.bmcl.2018.04.053

• Metabotropic glutamate receptor subtype 5 (mGlu(5))
• Negative allosteric modulator (NAM)
• Central nervous system (CNS)
• G protein-coupled receptor (GPCR)
• Quinoline

Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu(5) negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinolme-8-carboxamide mGlu(5) NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu(5) assay, and an exemplar analog 27 was <60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.

• 出版日期2018-6-1