Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis.
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
Hu
Baihua
B
Chemical and Screening Science, Cardiovascular and Metabolic Disease, and Bio Transformation and Disposition, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. hub@wueth.com
Collini
Michael
M
Unwalla
Rayomand
R
Miller
Christopher
C
Singhaus
Robert
R
Quinet
Elaine
E
Savio
Dawn
D
Halpern
Anita
A
Basso
Michael
M
Keith
James
J
Clerin
Valerie
V
Chen
Liang
L
Resmini
Christine
C
Liu
Qiang-Yuan
QY
Feingold
Irene
I
Huselton
Christine
C
Azam
Farooq
F
Farnegardh
Mathias
M
Enroth
Cristofer
C
Bonn
Tomas
T
Goos-Nilsson
Annika
A
Wilhelmsson
Anna
A
Nambi
Ponnal
P
Wrobel
Jay
J
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy*; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics; D004355:Drug Stability; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol; C025136:phenylacetic acid