ABSTRACT
The mTOR kinase regulates a variety of critical cellular processes and has become a target for the treatment of various cancers. Using a combination of property-based drug design and Free-Wilson analysis, we further optimized a series of selective mTOR inhibitors based on the (S)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one scaffold. Our efforts resulted in 14c, which showed similar in vivo efficacy compared to previous lead 1 at 1/15 the dose, a result of its improved drug-like properties.
ABSTRACT
Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Enzyme Activators/pharmacology , Glucokinase/metabolism , Indazoles/pharmacology , Administration, Oral , Allosteric Regulation/drug effects , Animals , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Enzyme Activators/administration & dosage , Enzyme Activators/chemistry , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Glucose Tolerance Test , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Mice , Mice, Inbred C57BL , Mice, Obese , Models, Molecular , Molecular Structure , Potassium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.
Subject(s)
Aminopeptidases/antagonists & inhibitors , Body Weight/drug effects , Drug Discovery , Enzyme Inhibitors/pharmacology , Glycoproteins/antagonists & inhibitors , Indoles/pharmacology , Obesity/drug therapy , Pyrazoles/pharmacology , Administration, Oral , Aminopeptidases/metabolism , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Glycoproteins/metabolism , Humans , Indoles/administration & dosage , Indoles/chemistry , Methionyl Aminopeptidases , Mice , Mice, Obese , Models, Molecular , Molecular Structure , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.
Subject(s)
Aminopeptidases/antagonists & inhibitors , Body Weight/drug effects , Drug Discovery , Enzyme Inhibitors/pharmacology , Glycoproteins/antagonists & inhibitors , Indazoles/pharmacology , Obesity/drug therapy , Administration, Oral , Aminopeptidases/metabolism , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Glycoproteins/metabolism , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Methionyl Aminopeptidases , Mice , Mice, Obese , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.