Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates.
In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.
Lundquist
Joseph T
JT
Department of Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. lundquj@wyeth.com
Harnish
Douglas C
DC
Kim
Callain Y
CY
Mehlmann
John F
JF
Unwalla
Rayomand J
RJ
Phipps
Kristin M
KM
Crawley
Matthew L
ML
Commons
Thomas
T
Green
Daniel M
DM
Xu
Weixin
W
Hum
Wah-Tung
WT
Eta
Julius E
JE
Feingold
Irene
I
Patel
Vikram
V
Evans
Mark J
MJ
Lai
Kehdih
K
Borges-Marcucci
Lisa
L
Mahaney
Paige E
PE
Wrobel
Jay E
JE
D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011973:Receptors, LDL / Q000235:genetics; D012995:Solubility; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
D001381:Azepines; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D007211:Indoles; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C547955:isopropyl 8-fluoro-1,1-dimethyl-3-(4-(3-morpholin-4-ylpropoxy)benzoyl)-1,2,3,6-tetrahydroazepino(4,5-b)indole-5-carboxylate