Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR).
Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR agonist (EC(50) = 4 nM, Eff = 149%). Oral administration of 6m to LDLR(-/-) mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.
Flatt
Brenton
B
Department of Medicinal Chemistry, Exelixis Inc., 4757 Nexus Centre Drive, San Diego, California 92121, USA. bflatt@exelixis.com
Martin
Richard
R
Wang
Tie-Lin
TL
Mahaney
Paige
P
Murphy
Brett
B
Gu
Xiao-Hui
XH
Foster
Paul
P
Li
Jiali
J
Pircher
Parinaz
P
Petrowski
Mary
M
Schulman
Ira
I
Westin
Stefan
S
Wrobel
Jay
J
Yan
Grace
G
Bischoff
Eric
E
Daige
Chris
C
Mohan
Raju
R
D000284:Administration, Oral; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000517:prevention & control; D001381:Azepines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins / Q000819:agonists*; D004195:Disease Models, Animal; D055808:Drug Discovery; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011973:Receptors, LDL / Q000172:deficiency; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
D001381:Azepines; D002784:Cholesterol; D004268:DNA-Binding Proteins; D007211:Indoles; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C540004:WAY-362450