120936-01-8Relevant academic research and scientific papers
Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (part 1)
Tremont, Samuel J.,Lee, Len F.,Huang, Horng-Chih,Keller, Bradley T.,Banerjee, Shyamal C.,Both, Scott R.,Carpenter, Andrew J.,Wang, Ching-Cheng,Garland, Danny J.,Huang, Wei,Jones, Claude,Koeller, Kevin J.,Kolodziej, Steve A.,Li, James,Manning, Robert E.,Mahoney, Matthew W.,Miller, Raymond E.,Mischke, Deborah A.,Rath, Nigam P.,Fletcher, Theresa,Reinhard, Emily J.,Tollefson, Michael B.,Vernier, William F.,Wagner, Grace M.,Rapp, Steve R.,Beaudry, Judy,Glenn, Kevin,Regina, Karen,Schuh, Joe R.,Smith, Mark E.,Trivedi, Jay S.,Reitz, David B.
, p. 5837 - 5852 (2007/10/03)
Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R′-2,3,4,5-tetrahydro-5-aryl-1- benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [14C] taurocholate (TC) in H14 cells. A 3R,4R,5R/3S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.
Pyrrole derivatives, process for their preparation and pharmaceutical compositions containing them
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, (2008/06/13)
Compounds of formula I, wherein, R1, R2, R3 and R5 have the meanings defined in the specification,G2 represents a chain -(CH2)z(W)y-, in which W has various meanings including C=O, and up to two of the methylene segments in the chain (CH2)zare optionally replaced by -NH- and one segment is optionally replaced by -O- or -(C=NR40)-, and the chain is optionally unsaturated and optionally substituted, and, A is a 5- or 6-membered ring or a bicyclic or tricyclic fused ring system, A being optionally substituted by various substituents,possess useful pharmacological properties, in particular as cardiotonics. Also described are processes for the preparation of compounds of formula I, pharmaceutical compositions containing them and methods of treatment involving their use.
