title: Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 1).
abstract: 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.
authors.affiliation: Department of Discovery Chemistry and Department of Cardiovascular Disease, Pharmacia, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Tremont
authors.forename: Len F
authors.initials: LF
authors.lastname: Lee
authors.forename: Horng-Chih
authors.initials: HC
authors.lastname: Huang
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Keller
authors.forename: Shyamal C
authors.initials: SC
authors.lastname: Banerjee
authors.forename: Scott R
authors.initials: SR
authors.lastname: Both
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carpenter
authors.forename: Ching-Cheng
authors.initials: CC
authors.lastname: Wang
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Garland
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Claude
authors.initials: C
authors.lastname: Jones
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Koeller
authors.forename: Steve A
authors.initials: SA
authors.lastname: Kolodziej
authors.forename: James
authors.initials: J
authors.lastname: Li
authors.forename: Robert E
authors.initials: RE
authors.lastname: Manning
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Mahoney
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Miller
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Mischke
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.forename: Theresa
authors.initials: T
authors.lastname: Fletcher
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Reinhard
authors.forename: Michael B
authors.initials: MB
authors.lastname: Tollefson
authors.forename: William F
authors.initials: WF
authors.lastname: Vernier
authors.forename: Grace M
authors.initials: GM
authors.lastname: Wagner
authors.forename: Steve R
authors.initials: SR
authors.lastname: Rapp
authors.forename: Judy
authors.initials: J
authors.lastname: Beaudry
authors.forename: Kevin
authors.initials: K
authors.lastname: Glenn
authors.forename: Karen
authors.initials: K
authors.lastname: Regina
authors.forename: Joe R
authors.initials: JR
authors.lastname: Schuh
authors.forename: Mark E
authors.initials: ME
authors.lastname: Smith
authors.forename: Jay S
authors.initials: JS
authors.lastname: Trivedi
authors.forename: David B
authors.initials: DB
authors.lastname: Reitz
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001582:Benzothiepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D001682:Biological Availability; D002460:Cell Line; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008647:Mesocricetus; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors*; D013656:Taurocholic Acid / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D001582:Benzothiepins; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid