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1.
Bioorg Med Chem ; 14(5): 1309-30, 2006 Mar 01.
Article in English | MEDLINE | ID: mdl-16263291

ABSTRACT

Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.


Subject(s)
Anticoagulants/pharmacology , Antithrombin III , Blood Coagulation/drug effects , Peptides/chemistry , Serine Proteinase Inhibitors/pharmacology , Administration, Oral , Animals , Anticoagulants/chemical synthesis , Antithrombin III/chemical synthesis , Antithrombin III/metabolism , Antithrombin III/pharmacology , Binding Sites , Blood Coagulation Tests , Dose-Response Relationship, Drug , Drug Design , Humans , Ligands , Microsomes, Liver/metabolism , Peptides/metabolism , Rats , Structure-Activity Relationship
2.
Bioorg Med Chem ; 13(12): 3927-54, 2005 Jun 02.
Article in English | MEDLINE | ID: mdl-15911309

ABSTRACT

Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N-oxide 6-6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1mg/kg of compound 75b.


Subject(s)
Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacokinetics , Administration, Oral , Animals , Anticoagulants/pharmacology , Binding Sites , Blood Coagulation/drug effects , Blood Coagulation Tests , Drug Design , Humans , Intestinal Absorption , Rats , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship
3.
J Med Chem ; 47(21): 5167-82, 2004 Oct 07.
Article in English | MEDLINE | ID: mdl-15456260

ABSTRACT

Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expected to be S4 binding element. Among this series, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine type 61 displayed orally potent anti-fXa activity and evident prolongation of prothrombin time (PT) with the moderate bioavailability in rats. The X-ray crystal analysis afforded an obvious binding mode that 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 6-chloronaphthalene respectively bound to S4 and S1 subsites. In this X-ray study, we discovered a novel intramolecular S-O close contact. Ab initio energy calculations of model compounds deduced that conformers with the most close S-O proximity were most stable. The Mulliken population analysis proposed that this energy profile was caused by both of electrostatic S-O affinity and N-O repulsion. The results of these calculations and X-ray analysis suggested a possibility that the restricted conformation effected the affinity to S4 subsite of fXa.


Subject(s)
Factor Xa Inhibitors , Pyridines/chemical synthesis , Thiazoles/chemical synthesis , Animals , Biological Availability , Crystallography, X-Ray , Factor Xa/chemistry , Humans , In Vitro Techniques , Male , Models, Molecular , Molecular Conformation , Protein Binding , Prothrombin Time , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Wistar , Thiazoles/chemistry , Thiazoles/pharmacology
4.
Bioorg Med Chem ; 12(21): 5579-86, 2004 Nov 01.
Article in English | MEDLINE | ID: mdl-15465335

ABSTRACT

Based on the both of results for X-ray studies of tetrahydrothiazolopyridine derivative 1c and FXV673, we synthesized a series of thiazol-5-ylpyridine derivatives containing pyridine N-oxide and 2-carbamoylthiazole units to optimize the S4 binding element. N-Oxidation of thiazol-5-ylpyridine increased the anti-fXa activity more than 10-fold independent on the position of N-oxide. The 4-pyridine N-oxide derivatives 3a and 3d excelled over the tetrahydrothiazolopyridine 1b in potency. 2-Methylpyridine N-oxide 3d exhibited 49-fold selectivity over thrombin. Our modeling study proposed a binding mode that the pyridine N-oxide ring of 3a stuck into the "cation hole" , and the oxide anion of 3a occupied in the almost same space to that of FXV673. From observations of the SAR and modeling studies, we suggested the possibilities that the formation of hydrogen bond with the oxide anion in the "cation hole" and the affinity of cationic pyridine ring to S4 subsite were responsible for increase in anti-fXa activity.


Subject(s)
Cyclic N-Oxides/chemical synthesis , Drug Design , Factor Xa Inhibitors , Pyridines/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Amidines/chemical synthesis , Amidines/pharmacology , Animals , Binding Sites/physiology , Cyclic N-Oxides/pharmacology , Factor Xa/metabolism , Humans , Male , Pyridines/pharmacology , Rats , Rats, Wistar , Serine Proteinase Inhibitors/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology
5.
Bioorg Med Chem Lett ; 14(11): 2935-9, 2004 Jun 07.
Article in English | MEDLINE | ID: mdl-15125963

ABSTRACT

In our investigation of factor Xa inhibitors, a series of 1-(6-chloronaphthalen-2-yl)sulfonyl-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)piperazines 3a-i were synthesized. In vitro inhibitory activities of the compounds against factor Xa and coagulation are summarized. Among the compounds, 3c and 3d, possessing a carbamoyl or N-methylcarbamoyl moiety, showed potent inhibitory activities when administered orally to rats.


Subject(s)
Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Protease Inhibitors/chemical synthesis , Pyridines/pharmacology , Administration, Oral , Animals , Anticoagulants/administration & dosage , Anticoagulants/pharmacology , Blood Coagulation Tests , Humans , Inhibitory Concentration 50 , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacology , Pyridines/chemical synthesis , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology
6.
Bioorg Med Chem ; 12(9): 2099-114, 2004 May 01.
Article in English | MEDLINE | ID: mdl-15080912

ABSTRACT

Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2S)-2-[4-[[(3S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats.


Subject(s)
Anticoagulants/chemistry , Anticoagulants/pharmacology , Factor Xa Inhibitors , Naphthalenes/chemistry , Naphthalenes/pharmacology , Propionates/chemistry , Propionates/pharmacology , Animals , Anticoagulants/chemical synthesis , Binding Sites , Magnetic Resonance Spectroscopy , Male , Naphthalenes/chemical synthesis , Propionates/chemical synthesis , Rats , Rats, Wistar , Spectrometry, Mass, Fast Atom Bombardment , Structure-Activity Relationship
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