RESUMO
The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.
Assuntos
Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Humanos , Testes de Mutagenicidade , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the "meta" channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators.
Assuntos
Amidas/química , Desenho de Fármacos , Receptores de Glucocorticoides/química , Amidas/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , NF-kappa B/metabolismo , Estrutura Terciária de Proteína , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismoRESUMO
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Reação de Arthus/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/uso terapêutico , Administração Oral , Compostos de Anilina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Quinase SykRESUMO
Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
Assuntos
Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Quinolinas/administração & dosagem , Quinolinas/química , Administração Oral , Animais , Bovinos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Masculino , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).
Assuntos
Benzamidas/síntese química , Pirazóis/síntese química , Receptores de Glucocorticoides/agonistas , Administração Oral , Animais , Benzamidas/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Prednisolona , Pirazóis/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.