NT-702 (parogrelil hydrochloride, NM-702), a novel and potent phosphodiesterase 3 inhibitor, suppress the asthmatic response in guinea pigs, with both bronchodilating and anti-inflammatory effects.
We evaluated the effects of NT-702 (parogrelil hydrochloride, NM-702, 4-bromo-6-[3-(4-chlorophenyl) propoxy]-5-[(pyridine-3-ylmethyl) amino] pyridazin-3(2H)-one hydrochloride), a selective phosphodiesterase 3 inhibitor, on the asthmatic response in guinea pigs. NT-702 at a concentration of 1 x 10(-7)M elevated the cyclic adenosine monophosphate content in prostaglandin E(2)-treated guinea pig tracheal smooth muscle cells. Leukotriene (LT) D(4)- and histamine-induced contraction of isolated guinea pig tracheal strips was inhibited by NT-702, with EC(50) values of 3.2 x 10(-7) and 2.5 x 10(-7)M, respectively. In an in vivo study, NT-702 suppressed LTD(4)-induced bronchoconstriction and the ovalbumin-induced immediate asthmatic response in guinea pigs through its bronchodilating effect. Furthermore, NT-702 also suppressed the ovalbumin-induced late asthmatic response, airway hyperresponsiveness, and the accumulation of inflammatory cells in the bronchoalveolar lavage fluid. These results suggest that NT-702 has an anti-inflammatory effect as well as a bronchodilating effect and might be useful as a novel potent therapeutic agent for the treatment of bronchial asthma, a new type of agent with both a bronchodilating and an anti-inflammatory effect.
Hori
Miyuki
M
Department of Pharmacology, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co Ltd, Saitama, Japan. miyuki.hori@po.rd.taisho.co.jp
Iwama
Takehisa
T
Asakura
Yumiko
Y
Kawanishi
Masafumi
M
Kamon
Junji
J
Hoshino
Akihiko
A
Takahashi
Shuya
S
Takahashi
Kenzo
K
Nakaike
Shiro
S
Tsuruzoe
Nobutomo
N
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000941:Antigens / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology; D001993:Bronchodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D017998:Leukotriene D4 / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D058987:Phosphodiesterase 3 Inhibitors; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D014132:Trachea / Q000187:drug effects
C516117:4-bromo-6-(3-(4-chlorophenyl)propoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone hydrochloride; D000893:Anti-Inflammatory Agents; D000941:Antigens; D001993:Bronchodilator Agents; D004791:Enzyme Inhibitors; D058987:Phosphodiesterase 3 Inhibitors; D011724:Pyridazines; D017998:Leukotriene D4; D006632:Histamine; D000242:Cyclic AMP; D015232:Dinoprostone