RESUMO
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.
RESUMO
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).
Assuntos
Antineoplásicos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/administração & dosagem , Tiazóis/química , Distribuição TecidualRESUMO
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.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Piridinas/farmacologia , Alquil e Aril Transferases/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/síntese química , Compostos Aza/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Haplorrinos , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/patologia , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Descoberta de Drogas/métodos , Farnesiltranstransferase/antagonistas & inibidores , Imidazóis/química , Piridinas/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Farnesiltranstransferase/metabolismo , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Piridinas/metabolismo , Piridinas/farmacologiaRESUMO
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.
Assuntos
RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hepatite C/enzimologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , RNA Viral/efeitos dos fármacos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Hepacivirus , Hepatite C/virologia , Concentração Inibidora 50 , Peso Molecular , Bibliotecas de Moléculas PequenasRESUMO
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.
Assuntos
Antivirais/farmacologia , Hepacivirus/enzimologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Antivirais/química , Modelos Moleculares , Ligação Proteica , Pirazóis/química , Pirimidinas/química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Biblioteca de Peptídeos , Zinco/química , Animais , Sítios de Ligação , Catálise , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/síntese química , Concentração Inibidora 50 , Camundongos , Células NIH 3T3 , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Tiazóis/farmacologia , Inibidores Enzimáticos/síntese química , Tiazóis/síntese químicaRESUMO
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.