Rational design and synthesis of small molecule, non-oligosaccharide selectin inhibitors: (alpha-D-mannopyranosyloxy)biphenyl-substituted carboxylic acids

T P Kogan; B Dupré; K M Keller; I L Scott; H Bui; R V Market; P J Beck; J A Voytus; B M Revelle; D Scott

doi:10.1021/jm00026a004

Rational design and synthesis of small molecule, non-oligosaccharide selectin inhibitors: (alpha-D-mannopyranosyloxy)biphenyl-substituted carboxylic acids

J Med Chem. 1995 Dec 22;38(26):4976-84. doi: 10.1021/jm00026a004.

Authors

T P Kogan¹, B Dupré, K M Keller, I L Scott, H Bui, R V Market, P J Beck, J A Voytus, B M Revelle, D Scott

Affiliation

¹ Department of Medicinal Chemistry and Immunology & Molecular Biology, Texas Biotechnology Corporation, Houston 77030, USA.

PMID: 8544173
DOI: 10.1021/jm00026a004

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.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Binding Sites
Biphenyl Compounds / chemical synthesis*
Biphenyl Compounds / pharmacology*
Calcium / chemistry
Calcium / metabolism
Carboxylic Acids / chemical synthesis*
Carboxylic Acids / chemistry
Carboxylic Acids / pharmacology*
Computer Graphics
Drug Design
E-Selectin / metabolism*
HL-60 Cells
Humans
Immunoglobulin G / genetics
Immunoglobulin G / metabolism
Lewis Blood Group Antigens / metabolism
Mannosides / chemical synthesis*
Mannosides / chemistry
Mannosides / pharmacology*
Mice
Models, Molecular
Oligosaccharides / metabolism
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Selectins / metabolism
Sialyl Lewis X Antigen
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Biphenyl Compounds
Carboxylic Acids
E-Selectin
Immunoglobulin G
Lewis Blood Group Antigens
Mannosides
Oligosaccharides
Recombinant Fusion Proteins
Selectins
Sialyl Lewis X Antigen
Calcium