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1.
Bioorg Med Chem Lett ; 19(8): 2179-85, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19297154

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 , Rats
3.
Bioorg Med Chem Lett ; 14(9): 2073-8, 2004 May 03.
Article in English | MEDLINE | ID: mdl-15080981

ABSTRACT

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/pharmacokinetics
4.
Bioorg Med Chem Lett ; 14(4): 983-7, 2004 Feb 23.
Article in English | MEDLINE | ID: mdl-15013006

ABSTRACT

Anthranilamides 4 and 5 were designed and synthesized as selective and orally bioavailable factor Xa inhibitors. Structural modifications aimed at lowering their lipophilicity were performed at the central phenyl ring and at the S4 binding biphenyl region by incorporating water solublizing substituents. The resulting compounds (e.g., 7, 8, 14, 30a, and 32b) are highly potent in vitro, and show improved activity in human plasma-based thrombin generation assay.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Factor Xa Inhibitors , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/pharmacology , Administration, Oral , Animals , Biological Availability , Drug Design , Drug Evaluation, Preclinical , Humans , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thrombosis/drug therapy , Thrombosis/prevention & control
5.
Bioorg Med Chem Lett ; 14(5): 1221-7, 2004 Mar 08.
Article in English | MEDLINE | ID: mdl-14980670

ABSTRACT

A variety of P4 motifs have been examined to increase the binding affinity and in vitro anticoagulant potency of our biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamide-based fXa inhibitors. Highly potent 2-naphthyl-P1 fXa inhibitors (K(i)< or =2 nM) with improved in vitro anticoagulant activity (2xTG< or =1 microM) and respectable pharmacokinetic properties have been discovered.


Subject(s)
Amides/chemistry , Antithrombin III/chemistry , Factor Xa Inhibitors , Pyrazoles/chemistry , Amides/metabolism , Amides/pharmacology , Animals , Antithrombin III/metabolism , Antithrombin III/pharmacology , Humans , Protein Binding , Pyrazoles/metabolism , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley
6.
Antimicrob Agents Chemother ; 47(12): 3810-4, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14638488

ABSTRACT

Among promising new targets for antimalarial chemotherapy are the cysteine protease hemoglobinases falcipain-2 and falcipain-3. We evaluated the activities of synthetic peptidyl aldehyde and alpha-ketoamide cysteine protease inhibitors against these proteases, against cultured Plasmodium falciparum parasites, and in a murine malaria model. Optimized compounds inhibited falcipain-2 and falcipain-3, blocked hemoglobin hydrolysis, and prevented the development of P. falciparum at nanomolar concentrations. The compounds were equally active against multiple strains of P. falciparum with varied sensitivities to standard antimalarial agents. The peptidyl inhibitors were consistently less active against vinckepain-2, the putative falcipain-2 and falcipain-3 ortholog of the rodent malaria parasite Plasmodium vinckei. The lead compound morpholinocarbonyl-leucine-homophenylalanine aldehyde, which blocked P. falciparum development at low nanomolar concentrations, was tested in a murine P. vinckei model. When infused continuously at a rate of 30 mg/kg of body weight/day, the compound delayed the progression of malaria but did not eradicate infections. Our data demonstrate the potent antimalarial activities of novel cysteine protease inhibitors. Additionally, they highlight the importance of consideration of the specific enzyme targets of animal model parasites. In the case of falcipains, differences between P. falciparum and rodent parasites complicate the use of the rodent malaria model in the drug discovery process.


Subject(s)
Antimalarials/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Plasmodium falciparum/drug effects , Aldehydes/pharmacology , Amides/pharmacology , Animals , Cysteine Endopeptidases/metabolism , Cysteine Endopeptidases/pharmacology , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship
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