Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 1).
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.
Tremont
Samuel J
SJ
Department of Discovery Chemistry and Department of Cardiovascular Disease, Pharmacia, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017, USA.
Lee
Len F
LF
Huang
Horng-Chih
HC
Keller
Bradley T
BT
Banerjee
Shyamal C
SC
Both
Scott R
SR
Carpenter
Andrew J
AJ
Wang
Ching-Cheng
CC
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
Fletcher
Theresa
T
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
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
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