Discovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonist

• Published in: Bioorganic & medicinal chemistry letters 2011-09, Vol.21 (18), p.5568-5572
• Main Authors: Sime, Mairi, Allan, Amanda C., Chapman, Paul, Fieldhouse, Charlotte, Giblin, Gerard M.P., Healy, Mark P., Lambert, Millard H., Leesnitzer, Lisa M., Lewis, Ann, Merrihew, Raymond V., Rutter, Richard A., Sasse, Rosemary, Shearer, Barry G., Wilson, Timothy M., Xu, Robert X., Virley, David J.
• Format: Article
• Language: English
• Subjects: agonists; Alzheimer’s disease; benzimidazole; Benzimidazoles; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; chemistry; Dose-Response Relationship, Drug; Drug Discovery; energy metabolism; glucose; homeostasis; Medical sciences; Molecular Structure; Neuropharmacology; Peroxisome proliferator-activated receptor; pharmacokinetics; Pharmacology. Drug treatments; PPAR gamma - antagonists & inhibitors; PPAR gamma - metabolism; PPARγ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.06.088

The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.