ABSTRACT
We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
Subject(s)
Acetates/pharmacology , Drug Discovery , Piperidones/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Sulfonamides/chemistry , Tumor Suppressor Protein p53/antagonists & inhibitors , Acetates/chemistry , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Conformation , Piperidones/chemistry , Protein Binding/drug effects , Proto-Oncogene Proteins c-mdm2/chemistry , Rats , Structure-Activity Relationship , Tumor Suppressor Protein p53/chemistryABSTRACT
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
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Subject(s)
Acetates/pharmacology , Antineoplastic Agents/pharmacology , Piperidones/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Acetates/chemistry , Administration, Oral , Antineoplastic Agents/chemistry , Biological Availability , Crystallography, X-Ray , Drug Discovery , Humans , Piperidones/chemistry , Protein ConformationABSTRACT
Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
Subject(s)
Acetates/chemical synthesis , Antineoplastic Agents/chemical synthesis , Piperidones/chemical synthesis , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Acetates/pharmacokinetics , Acetates/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Hepatocytes/metabolism , Humans , Macaca fascicularis , Mice , Mice, Nude , Models, Molecular , Molecular Conformation , Neoplasm Transplantation , Piperidones/pharmacokinetics , Piperidones/pharmacology , Protein Binding , Rats , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous , rho GTP-Binding Proteins/biosynthesisABSTRACT
A series of imidazole derivatives have been designed and optimized for CXCR3 antagonism, pharmacokinetic properties, and reduced formation of glutathione conjugates. Our efforts led to the discovery of potent CXCR3 antagonists with good pharmacokinetic properties. These compounds are useful tools for in vivo studies of CXCR3 function.
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Animals , Chromatography, High Pressure Liquid , Drug Design , Humans , Imidazoles/pharmacokinetics , Mice , Mice, Knockout , Rats , Receptors, CXCR3/genetics , Receptors, CXCR3/physiology , Structure-Activity RelationshipABSTRACT
A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo.
Subject(s)
Heterocyclic Compounds/pharmacology , Quinazolinones/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Animals , Chromatography, High Pressure Liquid , Humans , Quinazolinones/pharmacokinetics , Rats , StereoisomerismABSTRACT
A series of coumarin and pyranocoumarin analogues were evaluated in vitro for antiviral efficacy against measles virus (MV), strain Chicago. Of the 22 compounds tested for inhibition, six were found to have selectivity indices greater than 10. These were compounds 5-hydroxy-7-propionyloxy-4-propylcoumarin (2a), 5,7-bis(tosyloxy)-4-propylcoumarin (7); 5-hydroxy-4-propyl-7-tosyloxy-coumarin (8); 6,6-dimethyl-9-propionyloxy-4-propyl-2H,6H-benzo[1,2-b:3,4-b']dipyran-2-one (9); 6,6-dimethyl-9-pivaloyloxy-4-propyl-2H,6H-benzo[1,2-b:3,4-b']dipyran-2-one (10); and 7,8-cis-10,11,12-trans-4-propyl-6,6,10,11-tetramethyl-7,8,9-trihydroxy-2H,6H,12H-benzo[1 ,2-b:3,4-b':5,6-b'']tripyran-2-one (18). Three of the active drugs were propyl coumarin analogues (2a, 7 and 8), two were dipyranone or chromeno-coumarins (9 and 10), and one was a benzotripyranone with a coumarin nucleus (18). Some appeared to be rather specific and potent inhibitors of MV with EC50 values ranging from 0.2 to 50 microg/ml and the majority of the EC50 values being less than 5 pg/ml. The compounds inhibited an additional nine strains of MV, and in virucidal tests the drugs did not physically disrupt the virion to inhibit virus replication. The inhibitory activity for one of the compounds tested (7) was somewhat dependent on virus concentration and it was still active when added to cells up to 24 h after virus exposure. When used in combination with ribavirin, compound 7 appeared not to profoundly affect the antiviral efficacy of ribavirin or its cell-associated toxicity. However, a slightly antagonistic MV-inhibitory effect was observed at the highest concentration of ribavirin used in combination with most concentrations of compound 7 tested. This and related compounds may be valuable leads in the development of a potent and selective class of MV inhibitors that could be used in future in the clinic.
