RESUMO
In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.
Assuntos
Quinases Associadas a Receptores de Interleucina-1 , Piridonas , Conformação Molecular , Piridonas/farmacologia , Relação Estrutura-AtividadeRESUMO
In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.
Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/metabolismo , Quinazolinas/química , Aldeído Oxidase/metabolismo , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , Estabilidade de Medicamentos , Meia-Vida , Hepatócitos/metabolismo , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Assuntos
Indazóis/química , Receptores de AMPA/química , Tiofenos/química , Regulação Alostérica , Animais , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Indazóis/síntese química , Indazóis/farmacologia , Microssomos/metabolismo , Estrutura Terciária de Proteína , Ratos , Receptores de AMPA/metabolismo , Tiofenos/síntese química , Tiofenos/farmacologiaRESUMO
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.
Assuntos
Aminas/química , Aminas/farmacologia , Desenho de Fármacos , Pirazóis/química , Pirazóis/farmacologia , Receptores de AMPA/metabolismo , Regulação Alostérica , Aminas/síntese química , Aminas/farmacocinética , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Humanos , Modelos Moleculares , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos , Ratos Wistar , Receptores de AMPA/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In this article, we report our investigation of a phenomenon by which bridging morpholines across the ring with one-carbon tethers leads to a counterintuitive reduction in lipophilicity. This effect was also found to occur in piperazines and piperidines and lowered the measured log D7.4 of the bridged molecules by as much as -0.8 relative to their unbridged counterparts. As lowering lipophilicity without introducing additional heteroatoms can be desirable, we believe this potentially provides a useful tactic to improve the drug-like properties of molecules containing morpholine-, piperazine-, and piperidine-like motifs.
Assuntos
Carbono/química , Interações Hidrofóbicas e Hidrofílicas , Morfolinas/química , Piperazinas/química , Piperidinas/química , Modelos Moleculares , Estrutura MolecularRESUMO
A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.