title: Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 2).
abstract: 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.
authors.affiliation: Department of Discovery Chemistry and Department of Cardiovascular Disease, Pharmacia, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017, USA. horng-chih.huang@ Pfizer.com
authors.forename: Horng-Chih
authors.initials: HC
authors.lastname: Huang
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Tremont
authors.forename: Len F
authors.initials: LF
authors.lastname: Lee
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Keller
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carpenter
authors.forename: Ching-Cheng
authors.initials: CC
authors.lastname: Wang
authors.forename: Shyamal C
authors.initials: SC
authors.lastname: Banerjee
authors.forename: Scott R
authors.initials: SR
authors.lastname: Both
authors.forename: Theresa
authors.initials: T
authors.lastname: Fletcher
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: 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: D000042:Absorption; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001582:Benzothiepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001647:Bile Acids and Salts / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003460:Crystallization; D006801:Humans; D006813:Humidity; D008297:Male; D008647:Mesocricetus; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors*; D013656:Taurocholic Acid / Q000378:metabolism; D014961:X-Ray Diffraction
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