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/pharmacologyABSTRACT
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 RelationshipABSTRACT
A 57-year-old man with a 3-year history of chronic pancreatitis was admitted to our hospital with upper abdominal pain. Based on examination findings, the patient was diagnosed as having pseudocysts in the pancreatic body and the mediastinum that were associated with acute aggravation of chronic pancreatitis. Because of the patient refused an operation, he was submitted to conservative management including intramuscular injection with somatostatin analogue of 100 microg/day. On the 14th day of the treatment, pleural effusion and pseudocyst in the pancreatic head were additionally diagnosed based on the findings of computed tomography, magnetic resonance imaging and other examinations, and the dose of somatostatin analogue was increased to 200 microg/day. As a result, on the 28th day of the treatment, pancreatitis was inactivated, and the pseudocysts in the mediastinum and the pancreas disappeared. The patient has been followed up for 15 months, and there has been no recurrence.
Subject(s)
Mediastinal Cyst/drug therapy , Octreotide/therapeutic use , Pancreatic Pseudocyst/drug therapy , Humans , Male , Mediastinal Cyst/diagnostic imaging , Middle Aged , Pancreatic Pseudocyst/diagnostic imaging , Pancreatitis, Chronic/complications , RadiographyABSTRACT
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/pharmacologyABSTRACT
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 RelationshipABSTRACT
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.
