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 [(14)C]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.

A new 1,4-dihydropyridine 5a, containing a cyano group at the C3 position, was recently reported to possess excellent mineralocorticoid receptor (MR) antagonist in vitro potency and no calcium channel-blocker (CCB) activity. In the present study, we report the structure-activity relationships of this novel series of cyano ester dihydropyridines that resulted in R6 substituted analogues with improved metabolic stability while maintaining excellent MR antagonist activity and selectivity against other nuclear receptors. Further structure optimization with the introduction of five-membered ring heterocycles at R6 resulted in compounds with excellent MR antagonist potency and a suitable pharmacokinetic profile. In vivo studies of a promising tool compound in the Dahl salt-sensitive rat model of hypertension showed similar blood pressure (BP) reduction as the steroidal MR antagonist eplerenone, providing proof-of-concept (POC) for a nonsteroidal, orally efficacious MR antagonist.

In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.