RESUMO
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.
Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/síntese química , Naftiridinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Cães , Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Macaca fascicularis , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos , Relação Estrutura-Atividade , Células U937 , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/química , Bibliotecas de Moléculas Pequenas/síntese química , Animais , Células Cultivadas , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Estrutura Molecular , Isoformas de Proteínas/química , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.
Assuntos
Benzodiazepinas/química , Benzodiazepinas/farmacologia , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/metabolismo , Animais , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Cálcio/metabolismo , Linhagem Celular , Hepatócitos/metabolismo , Humanos , Medições Luminescentes , Obesidade/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Piperazine-bisamide analogs were discovered as partial agonists of human growth hormone secretagogue receptor (GHSR) in a high throughput screen. The partial agonists were optimized for potency and converted into antagonists through structure-activity relationship (SAR) studies. The efforts also led to the identification of potent antagonist with favorable PK profile suitable as a tool compound for in vivo studies.
Assuntos
Amidas/química , Fármacos Antiobesidade/química , Indóis/química , Piperazinas/química , Receptores de Grelina/antagonistas & inibidores , Amidas/síntese química , Amidas/uso terapêutico , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/uso terapêutico , Ensaios de Triagem em Larga Escala , Humanos , Indóis/síntese química , Indóis/uso terapêutico , Obesidade/tratamento farmacológico , Piperazinas/síntese química , Piperazinas/uso terapêutico , Ratos , Receptores de Grelina/metabolismo , Relação Estrutura-AtividadeRESUMO
Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolysis in vitro and reduce plasma FFA levels in vivo, suggesting that these allosteric modulators can serve as pharmacological tools for exploring the potential function of FFA2 in various disease conditions.
Assuntos
Acetamidas/síntese química , Receptores de Superfície Celular/agonistas , Receptores Acoplados a Proteínas G/agonistas , Acetamidas/química , Acetamidas/farmacocinética , Regulação Alostérica , Animais , AMP Cíclico/metabolismo , Descoberta de Drogas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.
Assuntos
PPAR delta/agonistas , PPAR gama/agonistas , Tiazóis/química , Animais , Simulação por Computador , Cristalografia por Raios X , PPAR delta/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.