Quinic acid derivatives as sialyl Lewis(x)-mimicking selectin inhibitors: design, synthesis, and crystal structure in complex with E-selectin.
A search for noncarbohydrate sLe(x) mimics led to the development of quinic acid derivatives as selectin inhibitors. At Wyeth we solved the first cocrystal structure of a small molecule, quinic acid, with E-selectin. In the cocomplex two hydroxyls of quinic acid mimic the calcium-bound fucose of the tetrasaccharide sLe(x). The X-ray structure, together with structure based computational methods, was used to design quinic acid based libraries that were synthesized and evaluated for their ability to block the interaction of sLex with P-selectin. A large number of analogues were prepared using solution-phase parallel synthesis. Selected compounds showed decrease in leukocyte rolling in the IVM mouse model. Compound 2 inhibited neutrophil influx in the murine TIP model and demonstrated good plasma exposure.
Chemical & Screening Sciences and Cardiovascular and Metabolic Disease Research, Wyeth, Cambridge, Massachusetts 02140, USA. nkaila@wyeth.com
Neelu
N
Kaila
William S
WS
Somers
Bert E
BE
Thomas
Paresh
P
Thakker
Kristin
K
Janz
Silvano
S
DeBernardo
Steve
S
Tam
William J
WJ
Moore
Ruiyang
R
Yang
Wojciech
W
Wrona
Patricia W
PW
Bedard
Deidre
D
Crommie
James C
JC
Keith
Desiree H H
DH
Tsao
Juan C
JC
Alvarez
Heyu
H
Ni
Erik
E
Marchese
John T
JT
Patton
John L
JL
Magnani
Raymond T
RT
Camphausen
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D019040:E-Selectin / Q000378:metabolism*; D005643:Fucose; D007601:Jugular Veins / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D007983:Lewis Blood Group Antigens; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000080506:Sialyl Lewis X Antigen; D020349:Surface Plasmon Resonance
D019040:E-Selectin; D007983:Lewis Blood Group Antigens; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D011801:Quinic Acid; D005643:Fucose