title: Benzimidazolone as potent chymase inhibitor: modulation of reactive metabolite formation in the hydrophobic (P1) region.
abstract: A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P(1) hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P(1) moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P(1) replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.
authors: Boehringer Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Ridgefield, CT 06877, USA. ho-yin.lo@boehringer-ingelheim.com
authors: Ho Yin
authors: HY
authors: Lo
authors: Peter A
authors: PA
authors: Nemoto
authors: Jin Mi
authors: JM
authors: Kim
authors: Ming-Hong
authors: MH
authors: Hao
authors: Kevin C
authors: KC
authors: Qian
authors: Neil A
authors: NA
authors: Farrow
authors: Daniel R
authors: DR
authors: Albaugh
authors: Danielle M
authors: DM
authors: Fowler
authors: Richard D
authors: RD
authors: Schneiderman
authors: E
authors: E
authors: Michael August
authors: Leslie
authors: L
authors: Martin
authors: Melissa
authors: M
authors: Hill-Drzewi
authors: Steven S
authors: SS
authors: Pullen
authors: Hidenori
authors: H
authors: Takahashi
authors: Stéphane
authors: S
authors: De Lombaert
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D010084:Oxidation-Reduction; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D011480:Protease Inhibitors; C014353:benzimidazolone; D053818:Chymases