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 synthe sized and evaluated in vitro as TXA(2) biosynthesis inhibitors. The ex periments were carried out using arachidonic acid (32.8 mu M) as a sub strate and horse platelet microsomes as sources of TXA(2) synthase. Th e presence of TXB2, a stable metabolite of TXA(2), was determined by R IA. The potency of active compounds (1.10(-4) < IC 50 < 1.10(-6) M) gr eatly depends on the length of the chain at the N-2 position on the py ridazine ring. Furthermore, enzyme inhibition in vitro is increased wi th 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-fluor o 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 synth esized pyridazinones and on prostaglandin H-2 (PGH(2)) suggesting spat ial features and volumes of TXA(2) synthase pharmacophore mode in thes e series of derivatives.