Structure-based design of potent retinoid X receptor alpha agonists.
A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.
Haffner
Curt D
CD
GlaxoSmithKline Research and Development, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA. curt.d.haffner@gsk.com
Lenhard
James M
JM
Miller
Aaron B
AB
McDougald
Darryl L
DL
Dwornik
Kate
K
Ittoop
Olivia R
OR
Gampe
Robert T
RT
Xu
H Eric
HE
Blanchard
Steve
S
Montana
Valerie G
VG
Consler
Tom G
TG
Bledsoe
Randy K
RK
Ayscue
Andrea
A
Croom
Dallas
D
D000179:Acrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D000882:Haplorhini; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D011924:Rats, Zucker; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D047488:Retinoid X Receptors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D014162:Transfection
C485111:3-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)tetrahydro-1-benzofuran-2-yl)-2-propenoic acid; D000179:Acrylates; D001572:Benzofurans; D007004:Hypoglycemic Agents; D008024:Ligands; D008055:Lipids; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors