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Potent MCH-1 receptor antagonists from cis-1,4-diaminocyclohexane-derived indane analogs |
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| Authors: | Yimin Qian Karin Conde-Knape Shawn D. Erickson Fiorenza Falcioni Paul Gillespie Irina Hakimi Francis Mennona Yonglin Ren Hamid Salari Sung-Sau So Jefferson W. Tilley |
| Affiliation: | 1. Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;2. Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States |
| Abstract: | Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation. |
| Keywords: | GPCR MCHR1 antagonist Fragment Bioisostere Conformation |
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