Design, Synthesis and Preliminary Biological Evaluation of a Focused Combinatorial Library of Stereodiverse Carbohydrate-Scaold-Based Peptidomimetics Nicolas Moitessier, a Sylvie Dufour, c FrancËoise ChreÂtien, a Jean Paul Thiery, c Bernard Maigret b and Yves Chapleur a, * a Groupe SUCRES, Unite  Mixte 7565 CNRS-Universite  Henri Poincare Â-Nancy 1, BP 239, F-54506 Nancy-Vandoeuvre, France b Groupe de Biochimie The Âorique, Unite  Mixte 7565 CNRS-Universite  Henri Poincare Â-Nancy 1, BP 239, F-54506 Nancy-Vandoeuvre, France c Unite  Mixte 144, CNRS-Institut Curie, 24 Rue d'Ulm, F-75000 Paris, France Received 17 July 2000; accepted 4 October 2000 AbstractÐA focused combinatorial library of 126 mimetics of the RGD sequence based on sugar scaolds have been rationally constructed using molecular modeling, with a particular emphasis on the stereodiversity of the library. A liquid phase, mix and divide synthesis was used, active compounds being identi®ed by using orthogonal libraries and recursive deconvolution strategies. # 2001 Elsevier Science Ltd. All rights reserved. Introduction Combinatorial chemistry considerably changed the way of ®nding new molecules and also the way one is think- ing chemistry. 1 Most drug research is now concentrated on the ®nding of lead compounds by high throughput screening of large combinatorial libraries of chemically diverse compounds on a high number of pharmacologi- caltargets.Assoonasaleadcompoundisfound,amore restricted library is constructed by playing around the original hit compound structure to provide more active compounds.Allthisprocessseemstobecontradictoryto therationaldrugdesigninfastdevelopmentintheeighties whichled,withthehelpofsomeknowledgeofthebiolo- gicaltargetandofmolecularmodeling,tothedesignand synthesis of only a few candidate molecules. Betweenthesetwoapproaches,apparentlyfarfromeach other,thereshouldbeaspaceforanalternativeapproach, faster than the latter and less costly than the former. It appeared obvious that a rational library design, which maybecomputer-aided,wouldleaddirectlytoafocused library able to aord a few lead compounds in a very short time with great chances of success. We tried to make this idea real by studying a de®ned biological problem:theinhibitionofintegrin-mediatedadhesion,the dysfunctionofwhichisoftenrelatedtocancermetastasis, angiogenesis and osteoporosis. 2 Among others, the most biologicallyrelevant a IIb b 3 and a v b 3 integrinsrecognizethe shortArg-Gly-Asp(RGD)peptidicsequenceexhibitedby their proteic ligands, ®bronectin, vitronectin and other proteins of the extracellular matrix. 3 A major concern of the adhesion inhibition relies on the selectivity of a proteinvis-aÁ-visofaparticularintegrin.Thisselectivityis thought to be related to a bioactive conformation of the RGD sequence which could be speci®c for its receptor. 4 The design of soluble RGD mimetics has been largely investigated for the inhibition of the ®brinogen-a IIb b 3 bindingmediatedplateletaggregation. 5 Only a few selec- tive a v b 3 integrin antagonists have been found by screening non-peptide molecules. 6 Some peptide analo- gues have been proposed 7 and a new class of stereo- isomeric peptidic antagonists with high a v b 3 selectivity has been reported. 8 In this work, new selective RGD mimetics based on chiral scaolds using several original features including computer-aided design of the library and a solution phase combinatorial approach were devised by putting emphasis on stereodiversity. 0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(00)00256-X Bioorganic & Medicinal Chemistry 9 (2001) 511±523 *Corresponding author. Tel.: +33-383-91-23-55; fax: +33-383-91-24- 79; e-mail: Yves.Chapleur@meseb.uhp-nancy.fr