Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic α-Keto Heterocycles as Novel Inhibitors of Human Chymase

Abstract

We designed nonpeptidic chymase inhibitors based on the structure of a peptidic compound (1) and demonstrated that the combination of a pyrimidinone skeleton as a P3-P2 scaffold and heterocycles as P1 carbonyl-activating groups can function as a nonpeptidic chymase inhibitor. In particular, introduction of heterobicycles such as benzoxazole resulted in more potent chymase-inhibitory activity. Detailed structure-activity relationship studies on the benzoxazole moiety and substituents at the 2-position of the pyrimidinone ring revealed that 2r (Y-40079) had the most potent chymase-inhibitory activity (K(i) = 4.85 nM). This compound was also effective toward chymases of nonhuman origin and showed good selectivity for chymases over other proteases. Pharmacokinetic studies in rats indicated that 2r was absorbed slowly after oral administration and showed satisfactory bioavailability (BA) (T(max) = 6.0 +/- 2.3 h, BA = 19.3 +/- 6.6%, t(1/2) = 35.7 +/- 13.3 h). In conclusion, 2r is a novel, potent, and orally active chymase inhibitor which would be a useful tool in elucidating the pathophysiological roles of chymase.

Therapeutic potential of non-peptide chymase inhibitors

“…In 2000 Welfide patented [47] and in 2001 published details of the synthesis of α -keto heterocycle-substituted pyrimidinone derivatives [48] . Two of the 2-substituted pyrimidinone analogs were potent inhibitors of chymase [48] .…”

“…Two of the 2-substituted pyrimidinone analogs were potent inhibitors of chymase [48] . Thus, Compounds Y-40613 and Y-40079 ( Figure 2 ) inhibited human heart chymase with IC 50 values of 23 and 5 nM [48] .…”

“…Two of the 2-substituted pyrimidinone analogs were potent inhibitors of chymase [48] . Thus, Compounds Y-40613 and Y-40079 ( Figure 2 ) inhibited human heart chymase with IC 50 values of 23 and 5 nM [48] . These compounds also inhibited chymases from the dog, rat, and mouse but were less potent against bovine pancreatic chymotrypsin and human cathepsin B [48] .…”

Hydrogen bond studies in substituted N-(2-hydroxyphenyl)-2-[(4-methylbenzenesulfonyl)amino]acetamides

“…(p-toluenesulfonyl)-glycine-2-phenolamides) are useful intermediates in the synthesis of heterocyclic compounds with potential biological activity [9][10][11][12] . The molecular structure of these compounds is interesting because there are intramolecular O•••H•••N and C-H•••O interactions that constrain the geometry of the amide in the E,Z conformation (A in Scheme 1) 13 .…”

Synthesis and structural studies of N‐(p‐toluenesulfonyl)‐amino acid 3,5‐di‐tert‐butyl‐2‐phenolamides

“…We are interested in the synthesis and structural study of N-( p-toluenesulfonyl)-amino-acid-2-phenolamides 1-5 because they are useful intermediates for obtaining new heterocyclic compounds with important biological activity [1][2][3][4]. These compounds have constrained molecular structures where the arrangement of the intramolecular O· · ·H· · ·N interactions form a fused pseudobicyclic system with the amide group in the E,Z conformation (Scheme 1) [4].…”