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1.
Org Lett ; 23(16): 6439-6443, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34369790

RESUMO

A practical and efficient synthesis of α-heteroaryl propionic esters is developed by employing palladium-catalyzed α-heteroarylation of silyl ketene acetals, forming a wide variety of α-heteroaryl propionic esters with various substituents and functionalities in high yields. The success of this transformation is credited to the development of the bulky P,P═O ligand. The method has provided an efficient synthesis of α-heteroaryl propionic acids.

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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