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.

Abstract

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.

• Authors: Miyuki Hori, Takehisa Iwama, Yumiko Asakura, Masafumi Kawanishi, Junji Kamon, Akihiko Hoshino, Shuya Takahashi, Kenzo Takahashi, Shiro Nakaike, Nobutomo Tsuruzoe
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 618 Issue 1-3 Pg. 63-9 (Sep 15 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19616537 (Publication Type: Journal Article)

Chemical References

• 4-bromo-6-(3-(4-chlorophenyl)propoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone hydrochloride
• Anti-Inflammatory Agents
• Antigens
• Bronchodilator Agents
• Enzyme Inhibitors
• Phosphodiesterase 3 Inhibitors
• Pyridazines
• Leukotriene D4
• Histamine
• Cyclic AMP
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antigens (immunology)
• Asthma (drug therapy, metabolism, pathology, physiopathology)
• Bronchoconstriction (drug effects, immunology)
• Bronchodilator Agents (pharmacology, therapeutic use)
• Cell Movement (drug effects)
• Cyclic AMP (metabolism)
• Dinoprostone (pharmacology)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Guinea Pigs
• Histamine (pharmacology)
• In Vitro Techniques
• Leukotriene D4 (pharmacology)
• Lung (drug effects, pathology)
• Male
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects, physiopathology)
• Phosphodiesterase 3 Inhibitors
• Pyridazines (pharmacology, therapeutic use)
• Trachea (drug effects)