ABSTRACT
Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
Subject(s)
Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Drug Discovery/methods , Factor Xa Inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Administration, Oral , Animals , Anticoagulants/administration & dosage , Benzamides/administration & dosage , Catalytic Domain/drug effects , Cell Line , Dogs , Dose-Response Relationship, Drug , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/genetics , Factor Xa/metabolism , Humans , Macaca fascicularis , Pyridines/administration & dosage , Rabbits , RatsABSTRACT
Parallel synthesis and iterative optimization led to the discovery of a series of potent and specific factor Xa inhibitors demonstrating excellent in vitro activity with promising pharmacokinetics.
Subject(s)
Antithrombin III/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Factor Xa Inhibitors , Antithrombin III/pharmacology , Enzyme Inhibitors/chemistry , Humans , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1 binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been examined.
Subject(s)
Benzamidines/pharmacology , Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Benzamidines/chemistry , Benzamidines/pharmacokinetics , Biological Availability , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokineticsABSTRACT
With the cloning of the P2Y12 receptor, the molecular basis for ADP-induced platelet aggregation is seemingly complete. Two platelet-bound ADP receptors, P2Y1 and P2Y12, operate through unique pathways to induce and sustain platelet aggregation via the glycoprotein (GP)IIb-IIIa integrin. P2Y1 operates via a glycoprotein q (Gq) pathway, activates phospholipase C, induces platelet shape change and is responsible for intracellular calcium mobilisation. P2Y12 inhibits adenylyl cyclase through a glycoprotein i (Gi)-dependent pathway, and is the target of the clinically used thienopyridines, ticlopidine (Ticlid, F. Hoffman-La Roche) and clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Synthelabo). In addition, the receptor is targeted by the ADP analogue AR-C66096, which is currently in Phase IIb clinical trials, as well as other non-nucleoside-based preclinical leads.
