title: Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties.
abstract: Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharmaceutical Research, Grenzacherstrasse, CH-4070 Basel, Switzerland. hans.richter@roche.com
authors.forename: Hans G F
authors.initials: HG
authors.lastname: Richter
authors.forename: G M
authors.initials: GM
authors.lastname: Benson
authors.forename: K H
authors.initials: KH
authors.lastname: Bleicher
authors.forename: D
authors.initials: D
authors.lastname: Blum
authors.forename: E
authors.initials: E
authors.lastname: Chaput
authors.forename: N
authors.initials: N
authors.lastname: Clemann
authors.forename: S
authors.initials: S
authors.lastname: Feng
authors.forename: C
authors.initials: C
authors.lastname: Gardes
authors.forename: U
authors.initials: U
authors.lastname: Grether
authors.forename: P
authors.initials: P
authors.lastname: Hartman
authors.forename: B
authors.initials: B
authors.lastname: Kuhn
authors.forename: R E
authors.initials: RE
authors.lastname: Martin
authors.forename: J-M
authors.initials: JM
authors.lastname: Plancher
authors.forename: M G
authors.initials: MG
authors.lastname: Rudolph
authors.forename: F
authors.initials: F
authors.lastname: Schuler
authors.forename: S
authors.initials: S
authors.lastname: Taylor
mesh_terms: D010129:4-Aminobenzoic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D010129:4-Aminobenzoic Acid; D001562:Benzimidazoles; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D062366:para-Aminobenzoates; D000099150:Receptor, Farnesoid X-Activated; C558287:4-(2-(2-(4-chlorophenyl)-5,6-difluorobenzoimidazol-1-yl)-2-cyclohexylacetylamino)-3-fluorobenzoic acid; C031000:benzimidazole