Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2553621 | Life Sciences | 2007 | 9 Pages |
Abstract
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.
Related Topics
Health Sciences
Medicine and Dentistry
Cardiology and Cardiovascular Medicine
Authors
Norihisa Ishiwata, Kazuo Noguchi, Masafumi Kawanishi, Yumiko Asakura, Miyuki Hori, Akiko Mitani, Yusuke Ito, Kanako Takahashi, Hiroshi Nishiyama, Norimasa Shudo, Shuya Takahashi, Kenzo Takahashi, Nobutomo Tsuruzoe, Shiro Nakaike,