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1.
J Med Chem ; 67(11): 8545-8568, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38805213

RESUMO

Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound 9 (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced in vivo mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).


Assuntos
Trifosfato de Adenosina , Doenças Autoimunes , Inibidores de Proteínas Quinases , Psoríase , TYK2 Quinase , Humanos , Animais , TYK2 Quinase/antagonistas & inibidores , TYK2 Quinase/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/química , Camundongos , Doenças Autoimunes/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Psoríase/tratamento farmacológico , Feminino , Descoberta de Drogas , Masculino , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Relação Estrutura-Atividade , Adulto
2.
J Med Chem ; 64(1): 343-353, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33399458

RESUMO

Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.


Assuntos
Fibrose Cística/tratamento farmacológico , Descoberta de Drogas , Piridinas/farmacologia , Piridinas/uso terapêutico , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Piridinas/química , Piridinas/farmacocinética , Ratos
3.
J Med Chem ; 61(4): 1425-1435, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29148763

RESUMO

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.


Assuntos
Agonistas dos Canais de Cloreto/química , Fibrose Cística/tratamento farmacológico , Descoberta de Drogas , Proteínas Mutantes/efeitos dos fármacos , Aminofenóis/farmacocinética , Animais , Agonistas dos Canais de Cloreto/farmacocinética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Mutação , Pirazóis/química , Pirazóis/farmacocinética , Quinolonas/farmacocinética , Ratos , Relação Estrutura-Atividade
4.
Chem Commun (Camb) ; (39): 4093-5, 2006 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-17024259

RESUMO

The catalytic asymmetric 1,2-addition of a series of arylboronic acids to 2,2,2-trifluoroacetophenones is described with high isolated yields (up to 96%) and good enantioselectivities (up to 83% ee) using a rhodium(I)/phosphoramidite catalyst.

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