N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization.
Bioorg Med Chem Lett
; 30(18): 127420, 2020 09 15.
Article
en En
| MEDLINE
| ID: mdl-32763808
ABSTRACT
A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (Kiâ¯=â¯4.02â¯nM; selectivity ratio cathepsin S/Kâ¯=â¯5.8; S/Lâ¯=â¯67) and 24 with a 4'-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (Kiâ¯=â¯35.5â¯nM; selectivity ratio cathepsin S/Kâ¯=â¯57; S/Lâ¯=â¯31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sulfonamidas
/
Catepsinas
/
Dipéptidos
/
Inhibidores Enzimáticos
/
Nitrilos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Alemania