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1.
J Med Chem ; 63(18): 10188-10203, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32407112

RESUMO

Toll-like receptor 8 (TLR8) recognizes pathogen-derived single-stranded RNA fragments to trigger innate and adaptive immune responses. Chronic hepatitis B (CHB) is associated with a dysfunctional immune response, and therefore a selective TLR8 agonist may be an effective treatment option. Structure-based optimization of a dual TLR7/8 agonist led to the identification of the selective TLR8 clinical candidate (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (GS-9688, (R)-7). Potent TLR8 agonism (IL-12p40 EC50 = 220 nM) and >100-fold TLR7 selectivity (IFN-α EC50 > 50 µM) was observed in human peripheral blood mononuclear cells (PBMCs). The TLR8-ectodomain:(R)-7 complex confirmed TLR8 binding and a direct ligand interaction with TLR8 residue Asp545. Oral (R)-7 had good absorption and high first pass clearance in preclinical species. A reduction in viral markers was observed in HBV-infected primary human hepatocytes treated with media from PBMCs stimulated with (R)-7, supporting the clinical development of (R)-7 for the treatment of CHB.


Assuntos
Antivirais/farmacologia , Hepatite B Crônica/tratamento farmacológico , Hexanóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Receptor 8 Toll-Like/agonistas , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/síntese química , Antivirais/metabolismo , Cristalografia por Raios X , Cães , Descoberta de Drogas , Vírus da Hepatite B/efeitos dos fármacos , Hexanóis/administração & dosagem , Hexanóis/síntese química , Hexanóis/metabolismo , Humanos , Macaca fascicularis , Estrutura Molecular , Domínios Proteicos , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos , Relação Estrutura-Atividade , Receptor 8 Toll-Like/metabolismo
2.
J Med Chem ; 61(21): 9473-9499, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30074795

RESUMO

Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.


Assuntos
Ciclofilinas/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Administração Oral , Antivirais/administração & dosagem , Antivirais/química , Antivirais/farmacocinética , Antivirais/farmacologia , Disponibilidade Biológica , Linhagem Celular , Ciclofilinas/química , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Hepacivirus/efeitos dos fármacos , Lactonas/administração & dosagem , Lactonas/química , Lactonas/farmacocinética , Lactonas/farmacologia , Modelos Moleculares , Conformação Proteica , Compostos de Espiro/administração & dosagem , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia
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