ABSTRACT
The discovery and optimization of imidazole cyclopropyl amime analogues as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, moderate liver microsome stability and PK properties.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Isocitrate Dehydrogenase/antagonists & inhibitors , Amines/chemistry , Amines/metabolism , Amines/pharmacokinetics , Amines/pharmacology , Animals , Cell Line , Drug Discovery , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Humans , Imidazoles/metabolism , Imidazoles/pharmacokinetics , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Mice , Microsomes, Liver/metabolism , Molecular Docking Simulation , Mutation , Rats , Structure-Activity RelationshipABSTRACT
CDK4/6 pathway is an attractive chemotherapeutic target for antitumor drug discovery and development. Herein, we reported the structure-based design and synthesis of a series of novel tetrahydronaphthyridine analogues as selective CDK4/6 inhibitors. Compound 5 was identified as a hit and then systematically structure optimization study was conducted. These efforts led to compound 28, which exhibited excellent in vitro potencies against CDK4/6 enzymatic activity with high selectivity over CDK1, and against Colo-205 cell growth. The compound demonstrated favorable in vitro metabolic and robust mice pharmacokinetic properties. In Colo-205 xenograft models, compound 28 showed potent tumor growth inhibition with acceptable toxic effects, which could serve as a novel anticancer agent for further preclinical study.
Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Tetrahydronaphthalenes/chemical synthesis , Animals , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Drug Design , Heterografts , Humans , Mice , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacologyABSTRACT
The discovery and optimization of various of indane amides as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, favorable PK properties and great selectivity against IDH1wt and IDH2R140Q.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Indans/pharmacology , Isocitrate Dehydrogenase/antagonists & inhibitors , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indans/chemical synthesis , Indans/chemistry , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Mice , Microsomes/chemistry , Microsomes/metabolism , Models, Molecular , Molecular Conformation , Mutation , Rats , Structure-Activity RelationshipABSTRACT
The discovery of a class of diheteroaromatic amines based on LY2835219 as cyclin-dependent kinase (CDK1/4/6) inhibitors was described. The series was found to have much more improved CDK1 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. The synthesis and structure-activity relationship studies of these compounds were reported. One promising compound was selected to evaluate as a novel lead compound after in vitro and in vivo profiling.
Subject(s)
Amines/pharmacology , Antineoplastic Agents/pharmacology , CDC2 Protein Kinase/antagonists & inhibitors , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Amines/administration & dosage , Amines/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Biological Availability , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/metabolism , Dose-Response Relationship, Drug , Drug Discovery , Drug Screening Assays, Antitumor , Humans , Male , Mice , Mice, Inbred ICR , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
A novel method for organocatalytic oxidation through oxidative enamine catalysis was developed with excellent compatibility for the direct syntheses of enals from simple saturated alcohols. By using this amine-catalyzed IBX-oxidation, a wide range of aromatic and aliphatic substituted enals were successfully generated in high yields and exclusively stereoselective E-geometry. Moreover, varying the solvents and/or the loading amounts of IBX allowed for the selective oxidation of alcohols and aldehydes. Importantly, the homologous application of this method provided a selective and efficient way of preparing various highly sensitive conjugated polyene frameworks, which are enriched in natural products.
ABSTRACT
Sodium-glucose co-transporters are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT-2) and the proximal tubule of the nephron (SGLT-1 and SGLT-2). They contribute to renal glucose reabsorption and most of renal glucose (about 90%) is reabsorbed by SGLT-2 located in the proximal renal tubule. Selectively inhibiting activity of SGLT-2 is an innovative therapeutic strategy for treatment of type 2 diabetes by enhancing urinary glucose excretion from the body. Therefore SGLT-2 inhibitors are considered to be potential antidiabetic drugs with an unique mechanism. This review will highlight some recent advances and structure-activity relationships in the discovery and development of SGLT-2 inhibitors including O-glycoside, C-glycoside, C, O-spiro glycoside and non glycosides.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Monosaccharides/chemical synthesis , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2/metabolism , Animals , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Glucosides/chemical synthesis , Glucosides/chemistry , Glucosides/pharmacology , Glycosides , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Molecular Structure , Monosaccharides/chemistry , Monosaccharides/pharmacology , Sodium-Glucose Transporter 1/metabolism , Structure-Activity RelationshipABSTRACT
Formyl peptide receptor-like 1 (FPRL1) is a structural homologue of FPR, which binds chemotactic peptides as small as three amino acids (e.g., fMet-Leu-Phe, fMLF) and activates potent bactericidal functions in neutrophils. In comparison, FPRL1 ligands include peptides of 6-104 amino acids, such as Trp-Lys-Tyr-Met-Val-[d]Met (WKYMVm) and other synthetic peptides. To determine the core peptide sequence required for FPRL1 activation, we prepared various analogues based on WKYMVm and evaluated their bioactivities in an FPRL1-transfected cell line. Although substitution of d-Met(6) resulted in loss of activity, removal of Val(5) together with d-Met(6) produced a peptide that retained most of the bioactivities of the parent peptide. The resulting peptide, WKYM, represents a core structure for an FPRL1 ligand. Further substitution of Lys(2) with Nle slightly improved the potency of the tetrapeptide, which selectively activates FPRL1 over FPR. Based on these structure-activity relationship studies, we propose a model in which the modified tetrapeptide Trp-Nle-Tyr-Met (WNleYM) binds to FPRL1 through aromatic interactions involving the side chains of Trp(1) and Tyr(3), hydrophobic interaction of Nle(2), and the thio-based hydrogen bonding of Met(4), with the respective residues in FPRL1 which have not been identified. The identification of the core sequence of a potent peptide agonist provides a structural basis for future design of peptidomimetics as potential therapeutic agents for FPRL1-related disorders.