RESUMO
4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).
Assuntos
Compostos Bicíclicos com Pontes/química , Cicloeptanos/química , Morfolinas/química , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Compostos Bicíclicos com Pontes/farmacologia , Cicloeptanos/farmacologia , Descoberta de Drogas/métodos , Humanos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-Atividade , Administração por Inalação , Animais , Classe Ia de Fosfatidilinositol 3-Quinase/química , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/administração & dosagem , Ligação de Hidrogênio , Isoquinolinas/química , Células Madin Darby de Rim Canino , RatosRESUMO
A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Doenças Respiratórias/tratamento farmacológico , Administração por Inalação , Animais , Disponibilidade Biológica , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Relação Dose-Resposta a Droga , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Doenças Respiratórias/metabolismo , Relação Estrutura-AtividadeRESUMO
The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.