Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase

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.

Influence of vitamin E on mast cell mediator release

“…However, in our experiments only the chymase activity tended to be decreased by vitamin E. This effect could be the result of a direct interaction of vitamin E with the enzyme. The inhibitory effect of nonpeptidic ketones on chymase but not on tryptase at the substrate binding site of chymase was described previously 21 . Such interactions are also conceivable with RRR‐α‐tocopherol and chymase.…”

Therapeutic potential of non-peptide chymase inhibitors

“…In 2001, Welfide described another 2-substituted pyrimidinone analog (Y-40018) ( Figure 2 ), which was more selective for human and dog chymase over rat and mouse chymase than the previous agents [49] . Y-40018 inhibited human chymase with an IC 50 value of 2.6 nM and had some bioavailability in rats (17%) and dogs (32%) [49] .…”

“…Y-40018 inhibited human chymase with an IC 50 value of 2.6 nM and had some bioavailability in rats (17%) and dogs (32%) [49] . The effects of the Welfide compounds in experimental disease models have not been reported.…”

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

“…However, due to a lack of inhibitors with both high inhibitory potency and metabolic stability, the pathophysiological role of chymase has not been fully elucidated yet. Similary, to the design of HLE inhibitors Akahoshi et al designed non-peptidic chymase inhibitors based on the predicted binding mode of the peptidic inhibitor Val-Pro-Phe-CF 3 (106) and demonstrated that in this structure the dipeptide Val-Pro can be replaced with the (5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetyl moiety, thus producing the constrained analog 107 [88] (Scheme 21). The potency of this type of chymase inhibitor was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties [89] (Table 11).…”