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排序方式: 共有257条查询结果,搜索用时 15 毫秒
81.
Varnes JG Wacker DA Jacobson IC Quan ML Ellis CD Rossi KA He MY Luettgen JM Knabb RM Bai S He K Lam PY Wexler RR 《Bioorganic & medicinal chemistry letters》2007,17(23):6481-6488
A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban. 相似文献
82.
Lam PY Adams JJ Clark CG Calhoun WJ Luettgen JM Knabb RM Wexler RR 《Bioorganic & medicinal chemistry letters》2003,13(10):1795-1799
In an effort to identify orally bioavailable factor Xa inhibitors, two isoxazolines libraries were prepared to scan for novel P1 ligands. From this work, 4-chloro-3-aniline was identified as a novel and potent benzamidine mimic. 相似文献
83.
Functional electrical stimulation is used to restore movement and function of paralyzed muscles by activating skeletal muscle artificially. An accurate and predictive mathematical model can facilitate the design of stimulation patterns that produce the desired force. The present study is a first step in developing a mathematical model for non-isometric muscle contractions. The goals of this study were to: (1) identify how our isometric force model's parameters vary with changes in knee joint angle, (2) identify the best knee flexion angle to parameterize this model, and (3) validate the model by comparing experimental data to predictions in response to a wide range of stimulation frequencies and muscle lengths. Results showed that by parabolically varying one of the free parameters with knee joint angle and fixing the other parameters at the values identified at 40 degrees of knee flexion, the model could predict the force responses to a wide range of stimulation frequencies and patterns at different muscle lengths. This work showed that the current isometric force model is capable of predicting the changes in skeletal muscle force at different muscle lengths. 相似文献
84.
Pruitt JR Pinto DJ Estrella MJ Bostrom LL Knabb RM Wong PC Wright MR Wexler RR 《Bioorganic & medicinal chemistry letters》2000,10(8):685-689
3,4,5-Trisubstituted isoxazolines (2) and isoxazoles (3) were prepared and evaluated for their in vitro and in vivo antithrombotic efficacy. They were compared to 3,5,5-trisubstituted isoxazolines (1) for Factor Xa selectivity and potency. They were also compared in an arterio-venous (A-V) shunt model of thrombosis. 相似文献
85.
Dominguez C Duffy DE Han Q Alexander RS Galemmo RA Park JM Wong PC Amparo EC Knabb RM Luettgen J Wexler RR 《Bioorganic & medicinal chemistry letters》1999,9(7):925-930
Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity. 相似文献
86.
Active porins were isolated and purified from the outer membranes of the gram-negative anaerobic rod Porphyromonas asaccharolytica and the aerobic coccobacillus Acinetobacter baumannii. The porins from both bacteria appear to be monomers when isolated and purified. Both porins exhibited decreased mobility on SDS-PAGE after boiling for 10 min in the sample buffer. After heating, their molecular weight is estimated at 43 kDa while without heating they run as proteins with a molecular weight of approximately 37 kDa. Due to their characteristic heat-modifiability, these proteins were named HMP (heat-modifiable protein)-P. asaccharolytica and HMP-A. baumannii. Amino acid analysis revealed both porins to be hydrophilic proteins. These proteins have been shown to be active in transporting sugars when incorporated into liposomes. The permeability of both porins for L-arabinose was less than that produced by the porin of Escherichia coli B. Permeability to high molecular weight disaccharides was lower than for small monosaccharides. Western blot analysis did not reveal any antigenic cross reaction between HMP-A. baumannii and the HMP-P. asaccharolytica. The results obtained in this study confirm that although these heat-modifiable proteins are pore forming proteins and have similar activity they differ in their antigenicity. 相似文献
87.
88.
The alpha-subunit of human pyruvate dehydrogenase (E(1)) is encoded by two separate genes. The gene located on chromosome X (PDHA-1) is expressed in somatic tissues, whereas the second gene (PDHA-2), located on chromosome 4, is expressed only in post-meiotic spermatogenic cells. A genomic fragment harboring the human gene encoding PDHA-2 has been isolated and approximately 800 nucleotides of the promoter region have been characterized. Functional studies of the promoter indicate the presence of both enhancer and repressor elements that are common to other genes that are only expressed in mature sperm. 相似文献
89.
90.