Rational design and synthesis of small molecule, non-oligosaccharide selectin inhibitors: (alpha-D-mannopyranosyloxy)biphenyl-substituted carboxylic acids.
J Med Chem
; 38(26): 4976-84, 1995 Dec 22.
Article
em En
| MEDLINE
| ID: mdl-8544173
ABSTRACT
The calcium dependent E-selectin/sialyl Lewisx (sLex) interaction plays a key role in inflammation where it mediates the rolling of leukocytes prior to firm adhesion and extravasation from the vasculature. A model of E-selectin/sLex binding, along with previously reported structure-activity relationships of sLex-related oligosaccharide, was used in the rational design of non-oligosaccharide inhibitors of this pivotal interaction. A palladium-mediated biaryl-coupling (Suzuki) reaction was used as the key step to prepare a number of substituted biphenyls which were assayed for their ability to inhibit the binding of E-, P-, and L-selectin-IgG fusion proteins to sLex expressed on the surface of HL60 cells. Some of the compounds developed had greater in vitro potency than the parent sLex tetrasaccharide and are currently being evaluated in in vivo models of inflammation to select a candidate for clinical development.
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Base de dados:
MEDLINE
Assunto principal:
Compostos de Bifenilo
/
Ácidos Carboxílicos
/
Anti-Inflamatórios não Esteroides
/
Selectina E
/
Manosídeos
Idioma:
En
Ano de publicação:
1995
Tipo de documento:
Article
País de afiliação:
Estados Unidos