Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene.
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Jonathan Y
JY
Bass
Justin A
JA
Caravella
Lihong
L
Chen
Katrina L
KL
Creech
David N
DN
Deaton
Kevin P
KP
Madauss
Harry B
HB
Marr
Robert B
RB
McFadyen
Aaron B
AB
Miller
Wendy Y
WY
Mills
Frank
F
Navas
Derek J
DJ
Parks
Terrence L
TL
Smalley
Paul K
PK
Spearing
Dan
D
Todd
Shawn P
SP
Williams
G Bruce
GB
Wisely
D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism; D018360:Crystallography, X-Ray; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004285:Dogs; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
D001786:Blood Glucose; D007555:Isoxazoles; D008024:Ligands; D009281:Naphthalenes; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C558292:GSK 2324; C031721:naphthalene