Synthesis of novel, potent, diol-based HIV-1 protease inhibitors via intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal.
J Med Chem
; 44(21): 3407-16, 2001 Oct 11.
Article
en En
| MEDLINE
| ID: mdl-11585446
The synthesis of novel, potent, diol-based HIV-1 protease inhibitors, having phenethyl groups (-CH(2)CH(2)Ph) in P1/P1' position is described. An intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal 16 was the key step in the synthesis. From this reaction sequence four carba analogues, compounds 8a, 8b, 9a, and 9b, were prepared, having the inverted configuration of one or both of the stereogenic centers carrying the diol hydroxyls as compared to the parent series represented by inhibitors 6 and 7. Inhibitor 8b was found to be a potent inhibitor of HIV-1 protease (PR), showing excellent antiviral activity in the cell-based assay and in the presence of 40% human serum. The absolute stereochemistry of the central diol of the potent inhibitor (8b) was determined from the X-ray crystallographic structure of its complex with HIV-1 PR.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
VIH-1
/
Inhibidores de la Proteasa del VIH
/
Amidas
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2001
Tipo del documento:
Article
País de afiliación:
Suecia
Pais de publicación:
Estados Unidos