RESUMO
The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
Assuntos
Ensaios de Triagem em Larga Escala/métodos , Proteínas/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Quimiocina CCL2/biossíntese , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas PequenasRESUMO
An efficient and highly convergent synthesis of the monomeric counterpart of the antitumor-antibiotic marine natural product marinomycin A was achieved by using optically active titanium complexes to control the configuration of the stereogenic centers, a highly stereo- and regioselective cross-metathesis to generate the (E)-configured C20-C21 double bond, and a Horner-Wadsworth-Emmons olefination followed by a Pd-catalyzed Stille cross-coupling to construct the tetraene moiety.
Assuntos
Alcenos/química , Antineoplásicos/síntese química , Macrolídeos/química , Antineoplásicos/química , Catálise , Dimerização , Estrutura Molecular , Paládio/químicaRESUMO
[structure: see text] The monomeric counterpart of marinomycin A, an antitumor-antibiotic marine natural product, was synthesized efficiently in 11 steps from the commercially available ethyl (R)-(-)-3-hydroxybutyrate. The strategy was highlighted by a crucial regio- and stereoselective cross-metathesis to form the C20-C21 double bond, enantioselective allyltitanations to control the configuration of the C17, C23, and C25 stereogenic centers, and a stereocontrolled construction of the tetraene moiety based on an original Horner-Wadsworth-Emmons olefination followed by a Pd-catalyzed cross-coupling.