Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 2).
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.
Huang
Horng-Chih
HC
Department of Discovery Chemistry and Department of Cardiovascular Disease, Pharmacia, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017, USA. horng-chih.huang@ Pfizer.com
Tremont
Samuel J
SJ
Lee
Len F
LF
Keller
Bradley T
BT
Carpenter
Andrew J
AJ
Wang
Ching-Cheng
CC
Banerjee
Shyamal C
SC
Both
Scott R
SR
Fletcher
Theresa
T
Garland
Danny J
DJ
Huang
Wei
W
Jones
Claude
C
Koeller
Kevin J
KJ
Kolodziej
Steve A
SA
Li
James
J
Manning
Robert E
RE
Mahoney
Matthew W
MW
Miller
Raymond E
RE
Mischke
Deborah A
DA
Rath
Nigam P
NP
Reinhard
Emily J
EJ
Tollefson
Michael B
MB
Vernier
William F
WF
Wagner
Grace M
GM
Rapp
Steve R
SR
Beaudry
Judy
J
Glenn
Kevin
K
Regina
Karen
K
Schuh
Joe R
JR
Smith
Mark E
ME
Trivedi
Jay S
JS
Reitz
David B
DB
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
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