Letters in Peptide Science 5: 75-78, 1998. KL UWER/ESCOM 9 1998KluwerAcademicPublishers. Printedin theNetherlands. 75 Synthesis of carbohydrate-based peptidomimetics as potential selective fibrinogen receptor antagonists Nicolas Moitessier a, Herv6 Minoux b, Bernard Maigret b, Fran~oise Chr6tien a & Yves Chapleur a,* a URA CNRS 486, Institut Nanc~ien de Chimie Moldculaire, and b URA CNRS 510, Universit~ Henri Poincar~, Nancy I, BP 239, F-54506 Vandoeuvre, France Received 1 May 1997; accepted 19 August 1997 Key words: antagonists, D-xylose scaffold, fibrinogen receptor, molecular modeling, peptidomimetics Summary Modeling studies of several known antagonists of the fibrinogen receptor have provided a theoretical pattern of the essential characteristics for high affinity and selectivity toward this receptor. Potentially active and selective antag- onists of the fibrinogen receptor were thus designed by computational comparison of their aqueous conformations with that of known selective antagonists, and synthesized by grafting suitable functional groups on a D-xylose scaffold. Introduction Vascular diseases, often due to a thrombotic plug, remain one of the main causes of mortality in devel- oped countries [1]. The control of platelet aggregation is a promising strategy of ischemic event treatment. Platelet aggregation mediated by fibrinogen binding on activated platelet receptor otnb/~3 [2] is responsive for thrombus growth; thus, inhibition of this adhe- sive binding is considered as a promising therapeutic strategy to control hemostasis [3]. Adhesive properties of fibrinogen are due to two RGD sequences and to a dodecapeptide carboxyl terminus [2]. The former sequence became the focus for platelet aggregation inhibitor design. To this end, RGD-containing pep- tides, RGD-like pseudopeptides and peptidomimetics have been designed and synthesized as antagonists of fibrinogen receptor [4]. However, given the high num- ber of RGD-dependent receptors, a selectivity toward the fibrinogen receptor is highly desirable. Some pep- tidomimetic antagonists show such a selectivity, but the origin of the selectivity of these potent peptides or peptidomimetics remains unclear. Taking advantage of the existence of such antagonists, we embarked recently on molecular modeling studies to shed light on the structural features responsible for this activity. Now we have tried to design potentially selective an- tagonists on the basis of these modeling studies by comparing their aqueous conformations with that of known selective antagonists, and we describe here their synthesis and the preliminary results of their biological activity. Materials and methods Molecular modeling was performed on Silicon Graph- ics computers using Biosym/MSI software packages. All calculations were done using the CVFF force field [5]. All solvents were dried and distilled prior to use. Ozonolysis was performed by bubbling a stream of ozone-containing oxygen through a solution of olefins at low temperature until no olefin was present as de- tected by TLC. Alkylation reactions were performed at 0 ~ in dry dimethylformamide (DMF) under dry nitrogen atmosphere, by treatment of the alcohol with sodium hydride, previously washed with dry THE The alkylating bromoacetate was added in one portion after 15 min and the mixture was stirred at 0 ~ until the re- action was complete. Analytical TLC was carried out on Merck 60 F254 silica gel. Column chromatography