PMID: 11312928Apr 21, 2001Paper

Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic difluoromethylene ketones as novel inhibitors of human chymase

Journal of Medicinal Chemistry
F AkahoshiN Nakamura

Abstract

Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P3-P2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K(i) of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.

References

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Citations

Apr 2, 2004·Biochimica Et Biophysica Acta·Anton PoliakovU Helena Danielson
Nov 1, 2003·Bioorganic & Medicinal Chemistry Letters·Hidekazu MasakiAtsuo Takahashi
Dec 7, 2002·Bioorganic & Medicinal Chemistry Letters·Yuuki KoideAtsuo Takahashi
Jul 27, 2001·Drug Discovery Today·D BarloccoD Tranter
Dec 5, 2002·Veterinary Dermatology·Thomas GueckHerbert Fuhrmann
Aug 5, 2008·Vascular Pharmacology·P D'Orléans-JusteE Simard
Aug 19, 2014·Protein Expression and Purification·Eliot T SmithDavid A Johnson
Sep 9, 2016·Angewandte Chemie·Ji-Wei GuXingang Zhang
May 9, 2018·Chemical Communications : Chem Comm·Ming LiYong-Min Liang
Feb 20, 2007·American Journal of Physiology. Heart and Circulatory Physiology·Mozow YusofRonald J Korthuis
Jun 16, 2011·Organic & Biomolecular Chemistry·Shigeyuki YamadaTakashi Ishihara
Dec 20, 2019·Journal of Medicinal Chemistry·Choi Yi LiSimon J de Veer
Jan 15, 2014·Journal of the American Chemical Society·Qiao-Qiao MinXingang Zhang
Jan 31, 2020·Journal of the American Chemical Society·Alastair N HerronJin-Quan Yu
Jul 25, 2019·The Journal of Organic Chemistry·Lin TangXiantao Ma

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