Rational design and synthesis of small molecule, non-oligosaccharide selectin inhibitors: (alpha-D-mannopyranosyloxy)biphenyl-substituted carboxylic acids.
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.
Kogan
T P
TP
Department of Medicinal Chemistry and Immunology & Molecular Biology, Texas Biotechnology Corporation, Houston 77030, USA.
Dupré
B
B
Keller
K M
KM
Scott
I L
IL
Bui
H
H
Market
R V
RV
Beck
P J
PJ
Voytus
J A
JA
Revelle
B M
BM
Scott
D
D
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003196:Computer Graphics; D015195:Drug Design; D019040:E-Selectin / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007983:Lewis Blood Group Antigens / Q000378:metabolism; D008362:Mannosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D009844:Oligosaccharides / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019087:Selectins / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D002264:Carboxylic Acids; D019040:E-Selectin; D007074:Immunoglobulin G; D007983:Lewis Blood Group Antigens; D008362:Mannosides; D009844:Oligosaccharides; D011993:Recombinant Fusion Proteins; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; D002118:Calcium