ABSTRACT
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.
ABSTRACT
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100â¯nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10â¯mpkâ¯=â¯0⯵Mâ¯h; F%â¯=â¯0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10â¯mpkâ¯=â¯26⯵Mâ¯h; F%â¯=â¯70).
Subject(s)
Antineoplastic Agents/pharmacology , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrrolidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A class of substituted 1-thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives was found to have potent anti-proliferative activity against a broad range of tumor cell lines. A compound from this class (14) was profiled across a broad panel of hematologic and solid tumor cancer cell lines demonstrating cell cycle arrest at the G0/G1 interphase and has potent anti-proliferative activity against a distinct and select set of cancer cell types with no observed effects on normal human cells. An example is the selective inhibition of human B-cell lymphoma cell line (BJAB). Compound 14 was orally bioavailable and tolerated well in mice. Synthesis and structure activity relationships (SAR) in this series of compounds are discussed.
Subject(s)
Antineoplastic Agents/pharmacology , Carboxylic Acids/pharmacology , Thiazoles/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Carboxylic Acids/administration & dosage , Carboxylic Acids/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , Structure-Activity Relationship , Thiazoles/administration & dosage , Thiazoles/chemistry , Tissue DistributionABSTRACT
Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Neoplasms, Experimental/drug therapy , Pyridines/pharmacology , Alkyl and Aryl Transferases/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Haplorhini , Humans , Mice , Mice, Transgenic , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.
Subject(s)
Drug Discovery/methods , Farnesyltranstransferase/antagonists & inhibitors , Imidazoles/chemistry , Pyridines/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Farnesyltranstransferase/metabolism , Humans , Imidazoles/metabolism , Imidazoles/pharmacology , Pyridines/metabolism , Pyridines/pharmacologyABSTRACT
The present paper describes a novel series of HCV RNA polymerase inhibitors based on a pyrazolo[1,5-a]pyrimidine scaffold bearing hydrophobic groups and an acidic functionality. Several compounds were optimized to low nanomolar potencies in a biochemical RdRp assay. SAR trends clearly reveal a stringent preference for a cyclohexyl group as one of the hydrophobes, and improved activities for carboxylic acid derivatives.
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hepatitis C/enzymology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , RNA, Viral/drug effects , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Evaluation, Preclinical , Hepacivirus , Hepatitis C/virology , Inhibitory Concentration 50 , Molecular Weight , Small Molecule LibrariesABSTRACT
A series of 4H-pyrazolo[1,5-a]pyrimidin-7-one derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase. A number of these compounds exhibited potent activity in enzymatic assay. The synthesis and structure-activity relationship are also described.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/enzymology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Antiviral Agents/chemistry , Models, Molecular , Protein Binding , Pyrazoles/chemistry , Pyrimidines/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , Structure-Activity RelationshipABSTRACT
Farnesyltransferase inhibitors identified from an ECLiPS library were optimized using solution-phase synthesis. X-ray crystallography of inhibited complexes was used to identify substructures that coordinate to the active site zinc. The X-ray structures were ultimately used to guide the design of second-generation analogs with FTase IC(50)s of less than 1.0 nM.
Subject(s)
Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Peptide Library , Zinc/chemistry , Animals , Binding Sites , Catalysis , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Farnesyltranstransferase/chemical synthesis , Inhibitory Concentration 50 , Mice , NIH 3T3 Cells , Structure-Activity RelationshipABSTRACT
Aminothiazole-based inhibitors designed for HCV polymerase display low micromolar potencies in biochemical assays. These compounds show a stringent preference for a cyclohexyl hydrophobe at the 2-amino position. The composition of these compounds suggests that they may be interacting at a recently discovered allosteric site on the polymerase.
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Thiazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Thiazoles/chemical synthesisABSTRACT
A series of novel N-cyanoguanidine tricyclic farnesyl protein transferase (FPT) inhibitors was prepared. Replacement of a piperidine amide-group with a N-cyanoguanidine functionality increased FPT activity. X-ray crystal structure determination of 42 complexed with FPT revealed differences in the interactions of the amide and N-cyanoguanidine groups with the protein.