ABSTRACT
Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4â¯t limited ghrelin-induced food intake.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Administration, Oral , Animals , Brain/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics , Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , Eating/drug effects , Ghrelin/pharmacology , Hydrogen Bonding , Indoles/chemistry , Indoles/metabolism , Inhibitory Concentration 50 , Mice , Mutagenesis , Protein Kinase Inhibitors/metabolismABSTRACT
Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.
Subject(s)
Orphan Nuclear Receptors/antagonists & inhibitors , Sulfonamides/chemical synthesis , Animals , Cell Line , Crystallography, X-Ray , Haplorhini , Humans , Liver X Receptors , Models, Molecular , Orphan Nuclear Receptors/genetics , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transcriptional Activation/drug effectsABSTRACT
PPARgamma-activating thiazolidinediones and carboxylic acids such as farglitazar exert their anti-diabetic effects in part in PPARgamma rich adipose. Both pro- and anti-adipogenic PPARgamma ligands promote glucose and lipid lowering in animal models of diabetes. Herein, we disclose representatives of an array of 160 farglitazar analogues with atypical inverse agonism of PPARgamma in mature adipocytes.
