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 intermittent claudication model.

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 (IC(50)=0.179 and 0.260 nM for PDE3A and 3B) more potently than cilostazol (IC(50)=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 (IC(50)=11 to 67 nM) and phenylephrine-induced rat aortic contraction (IC(50)=24 nM). Corresponding results for cilostazol were 4.1 to 17 microM and 1.0 microM, 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.

• 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
• Journal: Life sciences (Life Sci) Vol. 81 Issue 12 Pg. 970-8 (Sep 01 2007) ISSN: 0024-3205 [Print] Netherlands
• PMID: 17850826 (Publication Type: Journal Article)

Chemical References

• 4-bromo-6-(3-(4-chlorophenyl)propoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone hydrochloride
• Phosphodiesterase Inhibitors
• Pyridazines
• Tetrazoles
• Cilostazol

Topics

• Animals
• Body Temperature (drug effects)
• Cilostazol
• Hindlimb (blood supply)
• Humans
• Intermittent Claudication (drug therapy, physiopathology)
• Male
• Phosphodiesterase Inhibitors (therapeutic use)
• Platelet Aggregation (drug effects)
• Pyridazines (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Tetrazoles (pharmacology)
• Vasodilation (drug effects)
• Walking