RESUMO
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.
Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Pirróis/química , Tiazinas/química , Animais , Sítios de Ligação , Células CACO-2 , Cães , Desenho de Fármacos , Meia-Vida , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Simulação de Dinâmica Molecular , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Permeabilidade/efeitos dos fármacos , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/farmacocinética , Tiazinas/farmacologiaRESUMO
In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.
Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Terapia de Alvo Molecular , Fator 88 de Diferenciação Mieloide/genética , Quinazolinas/química , Quinazolinas/farmacologia , Administração Oral , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Feminino , Humanos , Quinases Associadas a Receptores de Interleucina-1/química , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Modelos Moleculares , Mutação , Conformação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/administração & dosagem , Quinazolinas/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
Assuntos
Antineoplásicos/farmacologia , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Feminino , Humanos , Quinases Associadas a Receptores de Interleucina-1/química , Linfoma Difuso de Grandes Células B/genética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos SCID , Mutação , Fator 88 de Diferenciação Mieloide/genética , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/química , Pirróis/química , Ratos Wistar , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The poor regioselectivity of the [4 + 2] cycloaddition of 3-azetidinones with internal alkynes bearing two alkyl substituents via nickel-catalyzed carbon-carbon activation is addressed using 1,3-enynes as substrates. The judicious choice of substitution on the enyne enables complementary access to each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines, which are important building blocks in medicinal chemistry endeavors.
RESUMO
Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.