NT-702 (parogrelil hydrochloride, NM-702), a novel and potent phosphodiesterase inhibitor, improves reduced walking distance and lowered hindlimb plantar surface temperature in a rat experimental inte

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• 作者：Norihisa Ishiwata ; Kazuo Noguchi ; Masafumi Kawanishi ; Yumiko Asakura ; Miyuki Hori ; Akiko Mitani ; Yusuke Ito ; Kanako Takahashi ; Hiroshi Nishiyama ; Norimasa Shudo ; Shuya Takahashi ; Kenzo Takahashi ; Nobu
• 关键词：Phosphodiesterase inhibitor ; Recombinant human protein ; Vasodilation ; Platelet aggregation ; Rats ; Intermittent claudication
• 刊名：Life Sciences
• 出版年：2007
• 出版时间：1 September 2007
• 年：2007
• 卷：81
• 期：12
• 页码：970-978
• 全文大小：1287 K

文摘

NT-702 (parogrelil hydrochloride, NM-702), 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-[(pyridin-3-ylmethyl)amino]pyridazin-3(2H)-one hydrochloride, a novel phosphodiesterase (PDE) inhibitor synthesized as a potent vasodilatory and antiplatelet agent, is being developed for the treatment of intermittent claudication (IC) in patients with peripheral arterial disease. We assessed the efficacy of NT-702 in an experimental IC model as compared with cilostazol and additionally investigated the pharmacological property in vitro and ex vivo. NT-702 selectively inhibited PDE3 (IC₅₀ = 0.179 and 0.260 nM for PDE3A and 3B) more potently than cilostazol (IC₅₀ = 231 and 237 nM for PDE3A and 3B) among recombinant human PDE1 to PDE6. NT-702 inhibited in vitro human platelet aggregation induced by various agonists (IC₅₀ = 11 to 67 nM) and phenylephrine-induced rat aortic contraction (IC₅₀ = 24 nM). Corresponding results for cilostazol were 4.1 to 17 μM and 1.0 μM, respectively. NT-702 (3 mg/kg or more) significantly inhibited ex vivo rat platelet aggregation after a single oral dose. For cilostazol, 300 mg/kg was effective. In a rat femoral artery ligation model, NT-702 at 5 and 10 mg/kg repeated oral doses twice a day (BID) for 13 days significantly improved the reduced walking distance while the lowered plantar surface temperature was improved at 2.5 mg/kg and more. Cilostazol also improved the walking distance and surface temperature at 300 mg/kg BID but significant difference was only observed for surface temperature on day 8. These results suggest that NT-702 can be expected to have therapeutic advantage for IC.