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
Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Lipoxins/chemical synthesis , Phenyl Ethers/chemical synthesis , Acute Disease , Animals , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Calcimycin , Dermatitis, Contact/drug therapy , Dermatitis, Contact/etiology , Drug Stability , Ionophores , Lipoxins/metabolism , Lipoxins/pharmacology , Male , Mice , Mice, Inbred BALB C , Oxidation-Reduction , Phenyl Ethers/metabolism , Phenyl Ethers/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Platelet Aggregation Inhibitors/therapeutic use , Purinergic P2 Receptor Antagonists , Animals , Humans , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Receptors, Purinergic P2/metabolismABSTRACT
Compound 1 was identified by high throughput screening as a novel PAI-1 inhibitor. Optimization of the B and C-segments of 1 resulted in a series of structurally simplified compounds with improved potency. The synthesis and SAR data of these compounds are presented here.
