ABSTRACT
We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing.
Subject(s)
Factor Xa Inhibitors , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Animals , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred ICR , Models, Molecular , Prodrugs/chemistry , Serine Proteinase Inhibitors/chemistry , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.
Subject(s)
Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Blood Coagulation Factor Inhibitors/chemical synthesis , Factor VIIa/antagonists & inhibitors , Lipoproteins/chemical synthesis , Methylamines/chemical synthesis , Methylamines/pharmacology , Thromboplastin/antagonists & inhibitors , Administration, Oral , Animals , Binding Sites , Biphenyl Compounds/chemistry , Blood Coagulation Factor Inhibitors/chemistry , Blood Coagulation Factor Inhibitors/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Hydrogen Bonding , Ligands , Lipoproteins/chemistry , Lipoproteins/pharmacology , Macaca fascicularis , Male , Methylamines/chemistry , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Structure , Protein Structure, Secondary , Sensitivity and Specificity , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Inhibition of tissue factor/factor VIIa complex (TF/FVIIa) is an attractive strategy for antithrombotic therapies. We began with an investigation of a non-amidine TF/FVIIa inhibitor based on a modification of amidine compound 1. Optimization of the substituents on the P1 phenyl portion of the compound 1 led to a neutral or less basic alternative for the 4-amidinophenyl moiety. By further optimization of the substituents on the central phenyl ring, a highly potent and selective TF/FVIIa inhibitor 17d was discovered.
Subject(s)
Factor VIIa/antagonists & inhibitors , Fibrinolytic Agents/chemistry , Thromboplastin/antagonists & inhibitors , Amidines/chemistry , Benzene Derivatives , Humans , Ligands , Protein Binding/drug effects , Structure-Activity RelationshipABSTRACT
Factor Xa (fXa) is a serine protease involved in the coagulation cascade, which has received great interest as a potential target for the development of new antithrombotic drugs. Herein we report a novel series of fXa inhibitors in which the 1,4-diazepane moiety was designed to interact with the S4 aryl-binding domain of the fXa active site. Compound 13 (YM-96765) showed potent fXa inhibitory activity (IC(50) = 6.8 nM) and effective antithrombotic activity without prolonging bleeding time.
Subject(s)
Aza Compounds/chemistry , Serine Proteinase Inhibitors/chemistry , Animals , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Dogs , Male , Mice , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacologyABSTRACT
Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure-activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described.
Subject(s)
Benzothiadiazines/chemistry , Benzothiadiazines/pharmacology , Factor Xa Inhibitors , Naphthalenes/chemistry , Naphthalenes/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Administration, Oral , Animals , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Benzothiadiazines/chemical synthesis , Biological Availability , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Conformation , Naphthalenes/chemical synthesis , Piperidines/chemical synthesis , Prothrombin Time , Saimiri , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacologyABSTRACT
Factor Xa (FXa) is a serine protease which plays a pivotal role in the coagulation cascade. The inhibition of FXa has received great interest as a potential target for the development of new antithrombotic drug. Herein we describe a series of novel 7-amidino-2-naphthoanilide and 7-amidino-2-naphthalensulfonanilide derivatives which are potent FXa inhibitors. These scaffolds are rigid and are allowed to adopt an L-shape conformation which was estimated as the active conformation based on a docking study of YM-60828 with FXa. Optimization of the side chain at the central aniline nitrogen of 7-amidino-2-naphthoanilide has led to several potent and orally active FXa inhibitors. 5h (YM-169964), the best compound of these series, showed potent FXa inhibitory activity (IC(50)=3.9nM) and effectively prolonged prothrombin time by 9.6-fold ex vivo at an oral dose of 3mg/kg in squirrel monkeys.
Subject(s)
Anilides/chemical synthesis , Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Administration, Oral , Anilides/pharmacokinetics , Anilides/pharmacology , Animals , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Biological Availability , Drug Design , Female , Male , Mice , Naphthalenes/chemical synthesis , Naphthalenes/pharmacokinetics , Naphthalenes/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Piperidines/pharmacology , Prothrombin Time , Saimiri , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Since Factor Xa (FXa) is well known to play a central role in thrombosis and hemostasis, inhibition of FXa is an attractive target for antithrombotic strategies. As a part of our investigation of a non-peptide, orally available FXa inhibitor, we found that a series of N-[(7-amidino-2-naphthyl)methyl]aniline derivatives possessed potent and selective inhibitory activities. Structure--activity relationship (SAR) of the substituent (R(1)) on the central aniline moiety suggested that increasing lipophilicity caused a detrimental effect on anticoagulant activity (prothrombin time assay) in plasma. Several compounds bearing a hydrophilic substituent in R(1) showed not only potent FXa inhibitory activities but also high anticoagulant activities. The best compound in this series was sulfamoylacetic acid derivative (YM-60828) which was a potent, selective and orally bioavailable FXa inhibitor and was chosen for clinical development.
