ABSTRACT
Factor Xa is a serine protease which activates thrombin (factor IIa) and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is, therefore, an important target for the design of anti-thrombotics. Both factor Xa and thrombin share sequence and structural homology with trypsin. As part of a factor Xa inhibitor-design program, a number of factor Xa inhibitors were crystallographically studied complexed to bovine trypsin. The structures of one diaryl benzimidazole, one diaryl carbazole and three diaryloxypyridines are described. All five compounds bind to trypsin in an extended conformation, with an amidinoaryl group in the S1 pocket and a second basic/hydrophobic moiety bound in the S4 pocket. These binding modes all bear a resemblance to the reported binding mode of DX-9065a in bovine trypsin and human factor Xa.
Subject(s)
Factor Xa Inhibitors , Trypsin/chemistry , Animals , Cattle , Crystallography, X-Ray , Drug Design , Electrochemistry , Humans , In Vitro Techniques , Macromolecular Substances , Models, Molecular , Molecular Conformation , Protein Binding , Protein ConformationSubject(s)
Amidines/chemical synthesis , Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Pyridines/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Administration, Oral , Amidines/chemistry , Amidines/pharmacokinetics , Amidines/pharmacology , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Benzylidene Compounds/chemical synthesis , Benzylidene Compounds/chemistry , Benzylidene Compounds/pharmacokinetics , Benzylidene Compounds/pharmacology , Binding Sites , Biological Availability , Cattle , Crystallography, X-Ray , Dogs , Drug Evaluation, Preclinical , Humans , Injections, Intravenous , Macaca fascicularis , Models, Molecular , Molecular Conformation , Papio , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Stereoisomerism , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacokinetics , Trypsin Inhibitors/pharmacologyABSTRACT
An arylamidine linker has been employed for the solid-phase synthesis of N-substituted amidinoaryloxypyridine analogs 2 via nucleophilic substitution on a fluoropyridyl template. Two novel N-substituted amidinoaryloxypyridine derivatives 2a and 2b were discovered via this approach.
Subject(s)
Factor Xa Inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyridines/chemistry , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis of amidinoaryloxy 9-benzyl-8-methyl-9H-purine, 7,8-dihydropteridine-6(5H)-one and 5,7-dihydropyrimido[4,5-b][1,4]oxazine-6-one inhibitors of Factor Xa is described. These compounds show nanomolar potency against FXa and maintain high selectivity over thrombin and trypsin.
Subject(s)
Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Pyrimidines/chemical synthesis , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacology , Binding Sites , Cattle , Drug Design , Factor Xa/chemistry , Humans , Indicators and Reagents , Kinetics , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Conformation , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacologyABSTRACT
We describe the synthesis and tissue biodistribution of two 21-[fluoro-18F]progestin 16 alpha, 17 alpha-furanyl ketals, potential agents for imaging progesterone receptor (PR)-positive breast tumors in humans, using positron emission tomography. 21-Fluro-16 alpha, 17 alpha-[(R)-(1'-alpha-furylmethylidene)dioxy]-19- norpregn-4-ene-3,20-dione (endo-10a) and 21-fluoro-16 alpha, 17 alpha-[(R)-(1'-alpha-furylethylidene)dioxy]-19- norpregn-4-ene-3,20-dione (endo-10b) were chosen for radiochemical synthesis from a series of seven novel progestin 16 alpha, 17 alpha-(furanyldioxolanes) on the basis of their high relative binding affinity to PR (190% and 173%, respectively, relative to R5020 = 100%), their low nonspecific binding (NSB) (log P o/w = 3.87 and 4.13, respectively), and their resulting high binding selectivity indices (BSI; i.e., the ratio of their PR binding affinity to nonspecific binding). Radiochemical synthesis of these two species in high radiochemical purity and at high effective specific activity was accomplished by treatment of the corresponding diastereomerically pure 21-trifluoromethanesulfonates with fluorine-18 anion. In tissue biodistribution studies in estrogen-primed immature female Sprague-Dawley rats, both [18F]-endo-10a and [18F]endo-10b demonstrated high PR-selective uptake in the principal target tissues, the uterus and the ovaries, and relatively low uptake in fat and bone. The metabolism at the 21-position in these progestins (as monitored by in vivo defluorination) appears to be less than that in other 21-fluoroprogestins; this may reflect steric inhibition of metabolism at this site due to the bulk of the furan-substituted dioxolane ring at the 16 alpha, 17 alpha-position. Comparison with other fluorine-18-labeled progestins shows that the PR-specific uptake in uterine tissue correlates with the BSI of the ligand and that the fat uptake correlates with the NSB of the ligand at high levels of statistical significance. These two dioxolanes may prove to be useful as breast tumor-imaging agents in humans.
Subject(s)
Progestins/metabolism , Receptors, Progesterone/metabolism , Animals , Female , Fluorine Radioisotopes , Ovary/metabolism , Progestins/chemical synthesis , Progestins/chemistry , Radioligand Assay , Radionuclide Imaging/methods , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity Relationship , Tissue Distribution , Uterus/metabolismABSTRACT
In order to diagnose patients with medium-chain acyl-CoA dehydrogenase deficiency with a noninvasive diagnostic technique such as positron emission tomography, we have developed a synthesis of [omega-11C]palmitic acid. The radiochemical synthesis was achieved by coupling an alkylfuran Grignard reagent (7) with [11C]methyl iodide, followed by rapid oxidative cleavage of the furan ring to the carboxylate using ruthenium tetraoxide. Tissue biodistribution studies in rats comparing [omega-11C]palmitic acid and [1-11C]palmitic acid show that the %ID/g and %ID/organ in the heart tissue after administration of [omega-11C]palmitic acid is approximately 50% greater than after administration of [1-11C]palmitic acid, due to the diminished metabolism of the [omega-11C]palmitic acid. These studies show as well, low uptake in nontarget tissues (blood, lung, kidney, and muscle). PET images of a dog heart obtained after administration of [omega-11C]-and [1-11C]palmitic acid show virtually identical uptake and distribution in the myocardium. The differing cardiac washout of labeled palmitates measured by dynamic PET studies may allow diagnosis of disorders in cardiac fatty acid metabolism.
