title: Application of a chymase inhibitor, NK3201, for prevention of vascular proliferation.
abstract: NK3201 is an orally active chymase inhibitor. Its inhibitory activity leads to formation of acyl-intermediate between active serine residue of the enzyme and di-ketone structure of NK3201. NK3201 inhibits human, dog and hamster chymases with IC(50) of 2.5, 1.2, and 28 nM, respectively. On the other hand, NK3201 does not inhibit other types of serine proteases, tryptase, thrombin, elastase, plasmin, and plasminogen activator. In dogs, at 8 h after oral administration of NK3201, 1 mg/kg, the drug levels in plasma, heart, and aorta reached 470, 195, and 78 nM, respectively. In a dog model NK3201, 5 mg/kg/day, increased chymase activity in grafted veins, and suppressed vascular proliferation. After balloon injury in dog vessels, chymase activity was increased locally, in the injured artery, and NK3201, 1 mg/kg/day was effective in preventing vascular proliferation. On the other hand, NK3201, unlike angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, did not affect blood pressure. These findings indicate that local angiotensin II production by chymase is involved only in vascular proliferation, as seen in the injured vessels. Therefore, NK3201 may be useful for preventing vascular proliferation without affecting blood pressure.
authors.affiliation: Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan. pha010@art.osaka-med.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D053818:Chymases; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006083:Graft Occlusion, Vascular / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D012697:Serine Endopeptidases / Q000378:metabolism*; D014652:Vascular Diseases / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000081:Acetamides; C437945:NK3201; D011480:Protease Inhibitors; D011743:Pyrimidines; D000804:Angiotensin II; D012697:Serine Endopeptidases; D053818:Chymases