Pharmacophore requirements in new series of pyridazinyl alkanoic acids, N-[(pyridazin-2-yl) alkyl] succinyl and glutaryl amides, inhibitors of thromboxane A 2 biosynthesis

• Published in: Prostaglandins, leukotrienes and essential fatty acids Vol. 56; no. 6; pp. 431 - 436
• Main Authors: Moreau, S., Coudert, P., Lasserre, B., Vallée-Goyet, D., Gardette, D., Navarro-Delmasure, C., Chanh, A.Pham Huu, Dossou-Gbete, V., Couquelet, J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 1997
• ISSN: 0952-3278; 1532-2823
• DOI: 10.1016/S0952-3278(97)90595-0

New series of 5-benzyl-6-methyl-4-oxo pyridazin-2-yl alkanoic acids, N-[(pyridazin-2-yl)alkyl] succinyl and glutaryl amides have been synthesized and evaluated in vitro as TXA 2 biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 μM) as a substrate and horse platelet microsomes as sources of TXA 2 synthase. The presence of TXB 2, a stable metabolite of TXA 2, was determined by RIA. The potency of active compounds (1.10 −4 < IC 50 < 1.10 −6 M) greatly depends on the length of the chain at the N-2 position on the pyridazine ring. Furthermore, enzyme inhibition in vitro is increased with the presence of a halogen atom on the aromatic moiety of the benzyl group at C-5. Compound 4f having a pentanoic side chain and a 4-fluoro benzyl moiety was the most active derivative with an IC 50 value of 6.69 × 10 −6 M. Molecular modelling studies were done on all the synthesized pyridazinones and on prostaglandin H 2 (PGH 2) suggesting spatial features and volumes of TXA 2 synthase pharmacophore mode in these series of derivatives.