Pharmacophore requirements in new series of pyridazinyl alkanoic acids, N-[(pyridazin-2-yl) alkyl] succinyl and glutaryl amides, inhibitors of thromboxane A2 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 TXA2 biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 microM) as a substrate and horse platelet microsomes as sources of TXA2 synthase. The presence of TXB2, a stable metabolite of TXA2, 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 H2 (PGH2) suggesting spatial features and volumes of TXA2 synthase pharmacophore mode in these series of derivatives.
Moreau
S
S
Groupe de Recherches en Pharmachochimie Laboratoire de Chimie Thérapeutique Faculté de Pharmacie 28, Clermont-Ferrand, France.
Coudert
P
P
Lasserre
B
B
Vallée-Goyet
D
D
Gardette
D
D
Navarro-Delmasure
C
C
Pham Huu Chanh
A
A
Dossou-Gbete
V
V
Couquelet
J
J
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006736:Horses; D066298:In Vitro Techniques; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D000577:Amides; D004791:Enzyme Inhibitors; D011724:Pyridazines; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase