178678-56-3Relevant articles and documents
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.
Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
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, (2008/06/13)
Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals.
Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
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, (2008/06/13)
Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals. Also provided are compositions and methods for combination therapy employing ileal bile acid transport inhibitors and EG Co-A reductase inhibitors for the treatment of hyperlipidemic conditions.
