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1.
Chem Pharm Bull (Tokyo) ; 55(2): 317-23, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17268108

ABSTRACT

In the course of development of factor Xa (FXa) inhibitors, we have found unique compounds containing an N,O- and an N,N-spiro acetal structure. It appeared that the difference in overall conformation due to the N,X-spiro acetal structure might be important for FXa inhibitory activity. Therefore, other N,X-spiro acetal structures, an N,S- and an N,SO2-spiro acetal, were developed as analogues of the N,X-spiro acetal structure. Compound 7b (N,S-spiro acetal structure) was found to have the strongest activity in these series of N,X-spiro acetal compounds, which had ever been synthesized.(4,5)).


Subject(s)
Acetals/chemistry , Antithrombin III/chemical synthesis , Nitrogen/chemistry , Oxygen/chemistry , Piperidines/chemical synthesis , Spiro Compounds/chemical synthesis , Anticoagulants/pharmacology , Antithrombin III/pharmacology , Molecular Conformation , Molecular Structure , Piperidines/pharmacology , Serine Proteinase Inhibitors/pharmacology , Spiro Compounds/pharmacology
2.
Chem Pharm Bull (Tokyo) ; 54(11): 1535-44, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17077550

ABSTRACT

We have already reported unique compounds containing a N,O-spiro acetal structure as an orally active factor Xa (FXa) inhibitor. This time, we described a N,N-spiro acetal structure as an analogue of the N,O-spiro acetal structure for an orally active FXa inhibitor. The synthesis of these analogues could be achieved in a similar fashion to the N,O-spiro acetal synthesis. Consequently, FXa inhibitory activity was increased and more active compounds could be found (M58163: IC50 = 0.61 nM, M58169: IC50 = 0.58 nM). Additionally, the absolute configuration could be determined by X-ray crystallography analysis (M58169: (R)-config.).


Subject(s)
Factor Xa Inhibitors , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidones/chemistry , Spiro Compounds/chemistry , Crystallography, X-Ray , Magnetic Resonance Spectroscopy/methods , Models, Molecular , Molecular Structure , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Naphthalenes/pharmacology , Piperazines/chemistry , Piperidones/chemical synthesis , Piperidones/pharmacology , Sensitivity and Specificity , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship
3.
Chem Pharm Bull (Tokyo) ; 52(4): 406-12, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15056953

ABSTRACT

In the course of development of factor Xa (FXa) inhibitor in an investigation involving the synthesis of 1-arylsulfonyl-3-piperazinone derivatives, we found new compounds containing a unique spiro skeleton. Among such compounds, (-)-7-[(6-chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-1'-(4-pyridinyl)-spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one (28, M55529) had activity more favorable than those of previously reported compounds. The inhibitory activity of M55529 for FXa is IC(50)=2 nM, with high selectivity for FXa over thrombin and trypsin.


Subject(s)
Factor Xa Inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Crystallography, X-Ray , Cyclization , Magnetic Resonance Spectroscopy , Mass Spectrometry , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacology
4.
Chem Pharm Bull (Tokyo) ; 52(4): 459-62, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15056966

ABSTRACT

Compounds containing an ethylenediamine structure in place of the piperazine ring of M55113 (1) and M55551 (2) were synthesized to investigate the effects of a piperazine moiety and evaluated for activity as factor Xa (FXa) inhibitors. Most such compounds, however, exhibited lower activity (1/10-1/100) than that of M55113 and M55551 as FXa inhibitors.


Subject(s)
Factor Xa Inhibitors , Piperazines/chemical synthesis , Piperazines/pharmacology , Indicators and Reagents , Magnetic Resonance Spectroscopy , Spectrophotometry, Infrared , Structure-Activity Relationship
5.
Chem Pharm Bull (Tokyo) ; 50(9): 1187-94, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12237534

ABSTRACT

Intravascular clot formation is an important event in a number of cardiovascular diseases. The prevention of blood coagulation has become a major target for new therapeutic agents. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. We have investigated substituents in the central part of a lead compound (3: M55113), and discovered that compound M55551 (34: (R)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic acid) is a potent inhibitor of FXa (IC(50)=0.006 microM), with high selectivity for FXa over trypsin and thrombin. The activity of this compound is ten times more powerful than the lead compound.


Subject(s)
Factor Xa Inhibitors , Arylsulfonates/chemical synthesis , Arylsulfonates/pharmacology , Crystallization , Hydrogen Bonding , Indicators and Reagents , Oxidation-Reduction , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacology
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