ABSTRACT
Utilizing modeling information from a recently resolved structure of human HIF-1alpha prolyl hydroxylase (EGLN1) and structure-based design, a novel series of imidazo[1,2-a]pyridine derivatives was prepared. The activity of these compounds was determined in a human EGLN1 assay and a limited SAR was developed.
Subject(s)
Procollagen-Proline Dioxygenase/antagonists & inhibitors , Pyridines/pharmacology , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases , Structure-Activity RelationshipABSTRACT
Structure-guided de novo drug design led to the identification of a novel series of substituted pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors. Pyridine carboxyamide derivatives bearing a substituted aryl group at the 5-position of the pyridine ring show appreciable activity, while constraining the side chain by placing a pyrazole carboxylic acid generated a potent lead series with consistent activity against EGLN-1.
Subject(s)
Drug Design , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Humans , Hypoxia-Inducible Factor-Proline DioxygenasesABSTRACT
An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values < 10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values < 100 nM) in a whole cell assay measuring IL-1beta production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Caspase Inhibitors , Peptides, Cyclic/pharmacology , Animals , Biological Availability , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , Inhibitory Concentration 50 , Molecular Mimicry , Peptides, Cyclic/chemical synthesis , Prodrugs/pharmacokinetics , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A new series of potent 8-hydroxyquinolines was designed based on the newly resolved X-ray crystal structure of EGLN-1. Both alkyl and aryl 8-hydroxyquinoline-7-carboxyamides were good HIF-1alpha prolyl hydroxylase (EGLN) inhibitors. In subsequent VEGF induction assays, these exhibited potent VEGF activity. In addition, this class of compounds did show the ability to stabilize HIF-1alpha.
Subject(s)
Drug Design , Oxyquinoline/analogs & derivatives , Oxyquinoline/pharmacology , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Hypoxia-Inducible Factor-Proline Dioxygenases , Oxyquinoline/chemical synthesis , Oxyquinoline/chemistry , Procollagen-Proline Dioxygenase/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of substituted quinoline analogs were designed and synthesized as potent and selective melanin concentrating hormone (MCH) antagonists. These analogs show potent (nM) activity (12a-k) with a moderate selectivity. Conversely, the conformationally constrained thienopyrimidinone analogs (18a-g) showed improved activity in MCH-1R and selectivity over 5HT2C.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Hypothalamic Hormones/antagonists & inhibitors , Melanins/antagonists & inhibitors , Pituitary Hormones/antagonists & inhibitors , Quinolines/chemical synthesis , Quinolines/pharmacology , Anti-Obesity Agents/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Pyrimidinones , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).
