ABSTRACT
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
Subject(s)
Cyclin-Dependent Kinase 4/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemical synthesis , Naphthyridines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Dogs , Drug Discovery , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Macaca fascicularis , Naphthyridines/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats , Structure-Activity Relationship , U937 Cells , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
A novel series of benzenesulfonanilide derivatives of 11ß-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11ß-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Anilides/chemistry , Aniline Compounds/chemistry , Enzyme Inhibitors/chemistry , Piperazines/chemistry , Sulfonamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 1/pharmacology , Anilides/chemical synthesis , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , HEK293 Cells , Humans , Molecular Conformation , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , TransfectionABSTRACT
A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.
Subject(s)
Acyltransferases/antagonists & inhibitors , Amides/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Acyltransferases/metabolism , Amides/chemistry , Amides/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , High-Throughput Screening Assays , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Human murine double minute 2 (MDM2) is a negative regulator of p53, which plays an important role in cell cycle and apoptosis. We report several optimizations to the synthesis of the chromenotriazolopyrimidine series of MDM2-p53 protein-protein interaction inhibitors. Additionally, the in vitro and in vivo stability, pharmacokinetic properties and solubility were improved through N-substitution.
Subject(s)
Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Pyrimidines/chemical synthesis , Tumor Suppressor Protein p53/antagonists & inhibitors , Animals , Drug Stability , Humans , Infusion Pumps , Inhibitory Concentration 50 , Molecular Structure , Pyrimidines/pharmacokinetics , Rats , Solubility , Structure-Activity RelationshipABSTRACT
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/chemistry , Enzyme Inhibitors/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Macaca fascicularis , Microsomes, Liver/metabolism , Rats , Structure-Activity RelationshipABSTRACT
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Quinolines/chemistry , Semicarbazides/chemistry , Thiourea/analogs & derivatives , Animals , Dogs , Female , Hepatocytes/metabolism , High-Throughput Screening Assays , Humans , I-kappa B Kinase/metabolism , Macaca mulatta , Male , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Semicarbazides/chemical synthesis , Semicarbazides/pharmacokinetics , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/chemistry , Thiourea/pharmacokineticsABSTRACT
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Semicarbazides/chemistry , Animals , Dogs , Female , High-Throughput Screening Assays , I-kappa B Kinase/metabolism , Male , Microsomes/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/chemistry , Rats , Semicarbazides/chemical synthesis , Semicarbazides/pharmacokinetics , Structure-Activity RelationshipABSTRACT
In this communication, human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11ß-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Sulfones/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Pharmacokinetics , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacokineticsABSTRACT
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Arylsulfonic Acids/chemical synthesis , Piperazines/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Arylsulfonic Acids/classification , Arylsulfonic Acids/pharmacology , Biological Availability , Cell Line , Crystallography, X-Ray , Enzyme Stability/drug effects , Enzyme Stability/physiology , Humans , Macaca fascicularis , Mice , Piperazines/classification , Piperazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Benzamides/pharmacology , Dose-Response Relationship, Drug , HeLa Cells , Humans , Macaca fascicularis , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the NADPH dependent interconversion of inactive cortisone to active cortisol. Excess 11beta-HSD1 or cortisol leads to insulin resistance and metabolic syndrome in animal models and in humans. Inhibiting 11beta-HSD1 activity signifies a promising therapeutic strategy in the treatment of Type 2 diabetes and related diseases. Herein, we report two highly potent and selective small molecule inhibitors of human 11beta-HSD1. While compound 1, a sulfonamide, functions as a simple substrate competitive inhibitor, compound 2, a triazole, shows the kinetic profile of a mixed inhibitor. Co-crystal structures reveal that both compounds occupy the 11beta-HSD1 catalytic site, but present distinct molecular interactions with the protein. Strikingly, compound 2 interacts much closer to the cofactor NADP+ and likely modifies its binding. Together, the structural and kinetic analyses demonstrate two distinctive molecular inhibition mechanisms, providing valuable information for future inhibitor design.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Metabolic Diseases/pathology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Amino Acid Sequence , Binding Sites , Biological Assay , Catalysis , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Humans , Kinetics , Metabolic Diseases/enzymology , Molecular Sequence Data , NADP/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/administration & dosage , Benzamides/chemical synthesis , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Benzamides/chemistry , Benzamides/metabolism , Cell Line , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Macaca fascicularis , Models, Animal , Models, Molecular , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A simple, scalable, and efficient one-pot methodology for the synthesis of 4,4-disubstituted cyclohexane beta-keto esters from benzylic nitriles or esters and methyl acrylate promoted by potassium tert-butoxide is described. The process relies on a tandem double Michael addition-Dieckmann condensation reaction, which results in the formation of three discrete carbon-carbon bonds in a single pot, including a quaternary center. The method allows for the convenient and rapid synthesis of a variety of 4-aryl-4-cyano-2-carbomethoxycyclohexanone and 4-aryl-2,4-biscarbomethoxycyclohexanone building blocks for use in natural products synthesis and medicinal chemistry.
Subject(s)
Cyclohexanones/chemistry , Esters/chemistryABSTRACT
Several dienes of varying steric bulk containing an enol carbonate have been synthesized and reacted selectively with ozone at the isolated double bonds. Rate measurements have been made for ozonolysis in a series of substituted cyclohexenes to demonstrate the unusually slow reactivity of the enol carbonate. Proton and carbon NMR chemical shifts have been presented to show that the enol carbonate is not particularly electron deficient in its double bond. Calculation of partial charges from the Mulliken population analysis shows good correlation with the NMR data. The results suggest a carbonate association with ozone that slows the rate of carbon-carbon bond cleavage.