title: Potent MCH-1 receptor antagonists from cis-1,4-diaminocyclohexane-derived indane analogs.
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.
authors.affiliation: Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. yiminqian81@gmail.com
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Erickson
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Falcioni
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.forename: Irina
authors.initials: I
authors.lastname: Hakimi
authors.forename: Francis
authors.initials: F
authors.lastname: Mennona
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Ren
authors.forename: Hamid
authors.initials: H
authors.lastname: Salari
authors.forename: Sung-Sau
authors.initials: SS
authors.lastname: So
authors.forename: Jefferson W
authors.initials: JW
authors.lastname: Tilley
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D003510:Cyclohexanes / Q000737:chemistry*; D006207:Half-Life; D007189:Indans / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D007536:Isomerism; D051379:Mice; D011485:Protein Binding; D051381:Rats; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D003510:Cyclohexanes; D007189:Indans; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; C506365:Cyclohexane; C031000:benzimidazole; C093582:indan