ABSTRACT
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
Subject(s)
Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Animals , Anticoagulants/chemical synthesis , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Antithrombin III/pharmacokinetics , Crystallography, X-Ray , Dogs , Humans , Male , Pyridones/pharmacokinetics , Pyrrolidines/pharmacokinetics , Rabbits , Rats , Structure-Activity RelationshipABSTRACT
A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.
Subject(s)
Antithrombin III/chemistry , Chemistry, Pharmaceutical/methods , Pyrrolidonecarboxylic Acid/pharmacology , Administration, Oral , Animals , Antithrombin III/pharmacology , Crystallization , Dogs , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Protein Binding , Pyrrolidonecarboxylic Acid/chemistry , Structure-Activity Relationship , Time FactorsABSTRACT
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
Subject(s)
Factor Xa Inhibitors , Factor Xa/chemistry , Glycine/analogs & derivatives , Glycine/chemistry , Serine Proteinase Inhibitors/chemistry , Crystallography, X-Ray , Humans , Molecular Structure , Protein ConformationABSTRACT
Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(pi+sigma) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.
Subject(s)
Piperazines/chemical synthesis , Renin/antagonists & inhibitors , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Caco-2 Cells , Cell Membrane Permeability , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Ether , Humans , Inhibitory Concentration 50 , Piperazine , Piperazines/pharmacokinetics , Piperazines/pharmacology , Solubility , Structure-Activity RelationshipABSTRACT
We have found that both enantiomeric configurations of the 6-alkoxymethyl-1-aryl-2-piperazinone scaffold display equipotent renin inhibition activity and similar SAR patterns. This enantiomeric flexibility is in contrast to a previously reported 3-alkoxymethyl-4-arylpiperidine scaffold.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Renin/antagonists & inhibitors , Binding Sites , Enzyme Inhibitors/chemistry , Indicators and Reagents , Molecular Conformation , Molecular Structure , Piperazines/chemistry , Protein Conformation , Renin/chemistry , StereoisomerismABSTRACT
Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).
