Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic triglyceride synthesis.
A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.
Wrobel
Jay
J
Chemical and Screening Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. wrobelj@wyeth.com
Steffan
Robert
R
Bowen
S Marc
SM
Magolda
Ronald
R
Matelan
Edward
E
Unwalla
Rayomand
R
Basso
Michael
M
Clerin
Valerie
V
Gardell
Stephen J
SJ
Nambi
Ponnal
P
Quinet
Elaine
E
Reminick
Jason I
JI
Vlasuk
George P
GP
Wang
Shuguang
S
Feingold
Irene
I
Huselton
Christine
C
Bonn
Tomas
T
Farnegardh
Mathias
M
Hansson
Tomas
T
Nilsson
Annika Goos
AG
Wilhelmsson
Anna
A
Zamaratski
Edouard
E
Evans
Mark J
MJ
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000096:biosynthesis* / Q000097:blood
D004268:DNA-Binding Proteins; D007191:Indazoles; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014280:Triglycerides