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Benzimidazolone as potent chymase inhibitor: modulation of reactive metabolite formation in the hydrophobic (P1) region |
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| Authors: | Lo Ho Yin Nemoto Peter A Kim Jin Mi Hao Ming-Hong Qian Kevin C Farrow Neil A Albaugh Daniel R Fowler Danielle M Schneiderman Richard D Michael August E Martin Leslie Hill-Drzewi Melissa Pullen Steven S Takahashi Hidenori De Lombaert Stéphane |
| Affiliation: | a Boehringer Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877, USA b Boehringer Ingelheim Pharmaceuticals Inc., Cardiometabolic Diseases, 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877, USA c Boehringer Ingelheim Pharmaceuticals Inc., High Throughput Biology, 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877, USA d Boehringer Ingelheim Pharmaceuticals Inc., Drug Discovery Support, 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877, USA |
| Abstract: | A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P1 hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P1 moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P1 replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome. |
| Keywords: | Chymase Cathepsin Serine protease GSH Indole Benzoisothiazole |
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