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.
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.
Ishiwata
Norihisa
N
Pharmacological Research Department, Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Minamisaitama-gun, Saitama, 349-0294, Japan. ishiwata@nissanchem.co.jp
Noguchi
Kazuo
K
Kawanishi
Masafumi
M
Asakura
Yumiko
Y
Hori
Miyuki
M
Mitani
Akiko
A
Ito
Yusuke
Y
Takahashi
Kanako
K
Nishiyama
Hiroshi
H
Shudo
Norimasa
N
Takahashi
Shuya
S
Takahashi
Kenzo
K
Tsuruzoe
Nobutomo
N
Nakaike
Shiro
S
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D000077407:Cilostazol; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007383:Intermittent Claudication / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D016138:Walking
C516117:4-bromo-6-(3-(4-chlorophenyl)propoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone hydrochloride; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D013777:Tetrazoles; D000077407:Cilostazol