Quinic acid derivatives as sialyl Lewis(x)-mimicking selectin inhibitors: design, synthesis, and crystal structure in complex with E-selectin.
Journal of medicinal chemistry 2005 Jun 30; 48(13):4346-57
Kaila N N, Somers W WS, Thomas B BE, Thakker P P, Janz K K, Debernardo S S, Tam S S, Moore W WJ, Yang R R, Wrona W W, Bedard P PW, Crommie D D, Keith J JC, Tsao D DH, Alvarez J JC, Ni H H, Marchese E E, Patton J JT, Magnani J JL, Camphausen R RT
Chemical & Screening Sciences and Cardiovascular and Metabolic Disease Research, Wyeth, Cambridge, Massachusetts 02140, USA. nkaila@wyeth.com
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.