ABSTRACT
Pim kinases are promising therapeutic targets for the treatment of hematological cancers. A potent Pim kinase inhibitor 7f, derived from meridianin C, was further optimized by the replacement of 2-aminopyrimidine with substituted benzene. The optimization of the C-3 and C-5 positions of indole yielded compound 43 with improved cellular potency and high selectivity against a panel of 14 different kinases.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hep G2 Cells , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Structure-Activity RelationshipABSTRACT
Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results in this series are rationalized based on analysis of selected compounds bound to renin, and the contribution of each molecular feature leading to the reduced P450 inhibition is quantified.
Subject(s)
Aspartic Acid/metabolism , Cytochrome P-450 CYP3A/metabolism , Protease Inhibitors/chemistry , Renin/antagonists & inhibitors , Aspartic Acid/chemistry , Binding Sites , Crystallography, X-Ray , Cytochrome P-450 CYP3A/chemistry , Cytochrome P-450 CYP3A Inhibitors/chemistry , Cytochrome P-450 CYP3A Inhibitors/metabolism , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protein Binding , Renin/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of meridianin C derivatives substituted at C-5 position were prepared. These derivatives were tested for their kinase inhibitory potencies against all three family members of the pim kinases (Pim-1, Pim-2 and Pim-3). In addition, their antiproliferative activity towards three human leukemia cell lines as MV4-11, Jurkat clone E6-1 and K562 has been evaluated. Structure activity relationships at C-3 and C-5 positions of indole were performed to better understand the mechanism behind the enhanced potency. Compound 7f, the most active compound of the series showed a single-digit nanomolar IC50 with selectivity towards Pim-1 kinase.
Subject(s)
Antineoplastic Agents/pharmacology , Ethylenediamines/pharmacology , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Caco-2 Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Ethylenediamines/chemical synthesis , Ethylenediamines/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Jurkat Cells , K562 Cells , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Structure-Activity RelationshipABSTRACT
Metabolic syndrome is a constellation of risk factors including hypertension, dyslipidemia, insulin resistance, and obesity that promote the development of cardiovascular disease. Metabolic syndrome has been associated with changes in the secretion or metabolism of glucocorticoids, which have important functions in adipose, liver, kidney, and vasculature. Tissue concentrations of the active glucocorticoid cortisol are controlled by the conversion of cortisone to cortisol by 11 ß -hydroxysteroid dehydrogenase type 1 (11 ß -HSD1). Because of the various cardiovascular and metabolic activities of glucocorticoids, we tested the hypothesis that 11 ß -HSD1 is a common mechanism in the hypertension, dyslipidemia, and insulin resistance in metabolic syndrome. In obese and lean SHR/NDmcr-cp (SHR-cp), cardiovascular, metabolic, and renal functions were measured before and during four weeks of administration of vehicle or compound 11 (10 mg/kg/d), a selective inhibitor of 11 ß -HSD1. Compound 11 significantly decreased 11 ß -HSD1 activity in adipose tissue and liver of SHR-cp. In obese SHR-cp, compound 11 significantly decreased mean arterial pressure, glucose intolerance, insulin resistance, hypertriglyceridemia, and plasma renin activity with no effect on heart rate, body weight gain, or microalbuminuria. These results suggest that 11 ß -HSD1 activity in liver and adipose tissue is a common mediator of hypertension, hypertriglyceridemia, glucose intolerance, and insulin resistance in metabolic syndrome.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/biosynthesis , Glucocorticoids/metabolism , Hypertension/enzymology , Hypertriglyceridemia/enzymology , Metabolic Syndrome/enzymology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Animals , Humans , Hypertension/metabolism , Hypertension/pathology , Hypertriglyceridemia/pathology , Insulin Resistance/genetics , Liver/enzymology , Liver/metabolism , Liver/physiopathology , Metabolic Syndrome/pathology , Obesity/blood , Obesity/enzymology , Obesity/physiopathology , Rats , Receptors, Leptin/genetics , Receptors, Leptin/metabolism , Weight GainABSTRACT
Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90α binding assay (IC(50) = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC(50) = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd × 5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice.