ABSTRACT
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Adenosine Triphosphate/metabolism , Administration, Oral , Animals , Binding Sites , Biological Availability , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/administration & dosage , Humans , Hydrogen Bonding , Isoenzymes/antagonists & inhibitors , Mice, Inbred C57BL , Multiple Sclerosis/drug therapy , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Phthalimides/chemistry , Structure-Activity RelationshipABSTRACT
The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.
Subject(s)
Diabetes Mellitus/drug therapy , Obesity/drug therapy , Quinazolinones/chemical synthesis , Receptors, Ghrelin/antagonists & inhibitors , Administration, Oral , Animals , Binding, Competitive , Blood Glucose/analysis , Cell Line , Eating/drug effects , Glucose Tolerance Test , Humans , Male , Mice , Mice, Inbred C57BL , Quinazolinones/chemistry , Quinazolinones/pharmacology , Radioligand Assay , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship , Weight Loss/drug effectsABSTRACT
Medicinal chemistry, as a field, has moved into new and unwelcome territory. How did we get here, and what might be the way out?
Subject(s)
Drug Discovery , Chemistry, Pharmaceutical , Combinatorial Chemistry Techniques , Hepacivirus/enzymology , Peptide Library , Protease Inhibitors/chemical synthesis , Small Molecule Libraries/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolismABSTRACT
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , 17-Hydroxysteroid Dehydrogenases/metabolism , Animals , Cell Line , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Macaca fascicularis , Pyrrolidinones/chemical synthesis , Rats , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesisABSTRACT
A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.
Subject(s)
Acetates/pharmacology , Oxazoles/chemistry , PPAR alpha/agonists , PPAR gamma/agonists , Acetates/administration & dosage , Acetates/chemical synthesis , Administration, Oral , Animals , Blood Glucose/drug effects , Cholesterol, HDL/blood , Cholesterol, HDL/drug effects , Drug Evaluation, Preclinical , Ligands , Mice , Mice, Mutant Strains , Mice, Obese , Molecular Structure , PPAR alpha/metabolism , PPAR gamma/metabolism , Structure-Activity Relationship , Triglycerides/blood , Triglycerides/metabolismABSTRACT
Elevation of plasma free fatty acids has been linked with insulin resistance and diabetes. Inhibition of lipolysis may provide a mechanism to decrease plasma fatty acids, thereby improving insulin sensitivity. Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores, and its inhibition may thus improve insulin sensitivity and blood glucose handling in type 2 diabetes. In rat adipocytes, forskolin-activated lipolysis was blocked by in vitro addition of a potent and selective HSL inhibitor or by prior treatment of the animals themselves. Antilipolytic effects also were demonstrated in overnight-fasted mice, rats, and dogs with species-dependent effects on plasma free fatty acid levels but with similar reductions in plasma glycerol being observed in all species. Inhibition of HSL also reduced hyperglycemia in streptozotocin-induced diabetic rats. The data support a connection between adipose tissue lipolysis and plasma glucose levels.
Subject(s)
Blood Glucose/metabolism , Lipids/blood , Sterol Esterase/antagonists & inhibitors , 3T3-L1 Cells , Adipocytes/metabolism , Animals , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/metabolism , Dogs , Fasting , Fatty Acids/analysis , Fatty Acids/metabolism , Glycerol/analysis , Glycerol/metabolism , Humans , Insulin/analysis , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/metabolism , Lipolysis , Male , Mice , Mice, Inbred BALB C , Rats , Rats, Sprague-Dawley , Rats, Wistar , Species Specificity , Sterol Esterase/genetics , Time FactorsABSTRACT
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.