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

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 mu M) as a substrate and horse platelet microsomes as sources of TXA(2) synthase. The presence of TXB2, 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 IC50 value of 6.69 x 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.