63675-91-2Relevant academic research and scientific papers
Antithrombotic agents
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Example 1A, (2010/01/31)
This application relates to novel compounds of formula I (and their pharmaceutically acceptable salts), as defined herein, processes and intermediates for their preparation, pharmaceutical formulations comprising the novel compounds of formula I, and the
Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives
Sall, Daniel J.,Bailey, Dianna L.,Bastian, Jolie A.,Buben, John A.,Chirgadze, Nickolay Y.,Clemens-Smith, Amy C.,Denney, Michael L.,Fisher, Matthew J.,Giera, Deborah D.,Gifford-Moore, Donetta S.,Harper, Richard W.,Johnson, Lea M.,Klimkowski, Valentine J.,Kohn, Todd J.,Lin, Ho-Shen,McCowan, Jefferson R.,Palkowitz, Alan D.,Richett, Michael E.,Smith, Gerald F.,Snyder, David W.,Takeuchi, Kumiko,Toth, John E.,Zhang, Minsheng
, p. 649 - 663 (2007/10/03)
A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit la led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 106 L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead la. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS,- 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
Antiestrogens. 2. Structure-Activity Studies in a Series of 3-Aroyl-2-arylbenzothiophene Derivatives Leading to thien-3-yl>phenyl>methanone Hydrochloride (LY156758), a Remarkably Effective Estrogen Antagonist with On...
Jones, Charles D.,Jevnikar, Mary G.,Pike, Andrew J.,Peters, Mary K.,Black, Larry J.,at al.
, p. 1057 - 1066 (2007/10/02)
In an effort to prepare nonsteroidal antiestrogens demonstrating greater antagonism and less intrinsic estrogenicity than those currently available, a series of 3-aroyl-2-arylbenzothiophene derivatives was synthesized.These compounds were prepared by Friedel-Crafts aroylation of appropriate O-protected 2-arylbenzothiophene nuclei with basic side-chain-bearing benzoyl chlorides followed by removal of the protective groups to provide the desired compounds containing both hydroxyl and basic side-chain functionality.A particularly useful method for the cleavage of aryl methoxy ethers without removal of (dialkylamino)ethoxy side chain functionality elsewhere in the molecule was found to be AlCl3/EtSH.The benzothiophene derivatives were tested for their ability to inhibit the growth-stimulating action of estradiol on the immature rat uterus.Seemingly minor changes in the side-chain amine moiety were found to have profound effects on the ability of the compounds to antagonize estradiol.Analogues having basic side chains containing cyclic (pyrrolidine, piperidine, and hexamethyleneamine) moieties were found to have less intrinsic estrogenicity and to antagonize estradiol action more completely than their noncyclic counterparts.The most effective antiestrogen in the series, compound 44, thien-3-yl>phenyl>methanone, elicited a modest uterotropic activity that did not increase with increasing dose.In antagonism of estradiol, 44 exhibited a degree of inhibition surpassing that of tamoxifen at any dose tested.The new benzothiophene antiestrogen was also shown to have high affinity for rat uterine cycloplasmic estrogen receptor and to be an inhibitor of the growth of DMBA-induced rat mammary tumors.
