RESUMO
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Descoberta de Drogas , Fenilalanina/farmacologia , Prolina/farmacologia , Triptofano/farmacologia , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carbazóis/administração & dosagem , Carbazóis/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fenilalanina/administração & dosagem , Fenilalanina/química , Prolina/administração & dosagem , Prolina/química , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Triptofano/administração & dosagem , Triptofano/químicaRESUMO
Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.
Assuntos
Compostos de Benzil/farmacologia , Compostos Heterocíclicos/farmacologia , Receptores do Ácido Retinoico/agonistas , Animais , Compostos de Benzil/química , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-Atividade , Receptor gama de Ácido RetinoicoRESUMO
Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.
RESUMO
Hydroxyl 1,2-diphenylethanamine analogs were identified as potent inhibitors of cholesterol ester transfer protein (CETP), a therapeutic target to raise HDL cholesterol. In an effort to improve the pharmaceutical properties in the previously disclosed DiPhenylPyridineEthanamine (DPPE) series, polar groups were introduced to the N-linked quaternary center. Optimization of analogues for potency, in vitro liability profile and efficacy led to identification of lead compound 16 which demonstrated robust pharmacodynamic effects in human CETP/apo-B100 dual transgenic mice.
Assuntos
Aminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Descoberta de Drogas , Aminas/síntese química , Aminas/química , Animais , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.
Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Benzamidas/farmacocinética , Benzilaminas/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , HDL-Colesterol/sangue , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inibidores , Cães , Descoberta de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Quinolinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
A series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein with aminoheterocycles appended onto the N-terminus of the chemotype were explored as urea mimetics. Potent compounds were discovered and were further optimized to improve metabolic stability and PXR transactivation profile.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Biomimética , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Estabilidade de Medicamentos , Etilaminas/síntese química , Etilaminas/química , Etilaminas/farmacologia , Compostos Heterocíclicos/química , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Ureia/químicaRESUMO
A novel series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein is described. Optimization of the urea moiety, particularly by incorporation of fluorine, is explored to balance in vitro metabolic stability with CETP potency in the whole plasma assay.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Aminas/sangue , Aminas/química , Aminas/metabolismo , Aminas/farmacologia , Animais , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Halogenação , Humanos , Camundongos , Piridinas/sangue , Piridinas/metabolismo , Ratos , Ureia/sangue , Ureia/metabolismoRESUMO
A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.
Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Anticolesterolemiantes/síntese química , Apolipoproteína B-100/antagonistas & inibidores , Apolipoproteína B-100/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença das Coronárias/tratamento farmacológico , Cricetinae , Descoberta de Drogas , Frequência Cardíaca/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Ratos , Estilbenos/síntese químicaRESUMO
SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.
Assuntos
Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Pirrolidinas/síntese química , Triazinas/síntese química , Triazinas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Janus Quinase 2/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Relação Estrutura-Atividade , Triazinas/químicaRESUMO
A G-Protein-coupled receptor-targeted library of aryloxypropanolamines and aryloxybutanolamines was efficiently executed using a novel, polymer-supported acyclic acetal linker, producing compounds in good yields and purities.
Assuntos
Aminas/síntese química , Desenho de Fármacos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Aminas/farmacologia , Técnicas de Química Combinatória , Reagentes de Ligações Cruzadas , Humanos , Polímeros , Propanolaminas , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.
Assuntos
Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Benzoxazóis/química , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
An efficient method for the solid-supported synthesis of 5-N-alkylamino and 5-N-arylamino pyrazoles is described. This method is general and mild and utilizes readily accessible resin-immobilized beta-ketoamides 2 as starting materials for the preparation of 1. Resin-immobilized beta-ketoamide, aryl-, or alkylhydazine and Lawesson's reagent are suspended in a mixture of THF/Py and heated at 50-55 degrees C to give a resin-bound 5-aminopyrazole, that is liberated from the solid support by treatment with TFA.
Assuntos
Aminas/química , Técnicas de Química Combinatória , Pirazóis/química , Pirazóis/síntese química , Estrutura MolecularRESUMO
The regiospecific syntheses of six monosaccharide scaffolds, 1-6, containing a carboxylic acid, an azido and a free hydroxyl group were accomplished through the utilization of a key intermediate, namely, methyl 3-azido-3-deoxy-beta-D-glucopyranoside (10). Scaffold 2 was also used in generating combinatorial libraries using solid-phase methodologies.