BIO(IRGANIC & MEDICINAL CHEMISTR Y Bioorganic & Medicinal Chemistry Letters 8 (1998) 2699-2704 LE'rrERS Pergamon TROPANE-BASED AMINO ACIDS FOR PEPTIDE STRUCTURE-FUNCTION STUDIES: INHIBITORS OF PLATELET AGGREGATION Philip E Thompson,* David L Steer, Marie-Isabel Aguilar, and Milton T W Hearn Centrefor Bioprocess Technology, Departmentof BiochemisPy and Molecular Biology, Monash University, Clayton 3168, Australia Received 17 April 1998; accepted 11 August 1998 Abstract: Novel tropane (azabicycloheptane) and azabicyclohexane containing amino acids have been prepared and incorporated into analogues of reported inhibitors of platelet aggregation. The influence of these central constraints upon biological activity suggest their utility in peptide structure function studies. © 1998 Published by ElsevierScience Ltd. All rights reserved. Introduction Novel, readily available amino acids that induce conformational constraint in peptides are important tools in peptide structure-function studies and peptidomimetic research.~ The potential of these amino acids has been amplified in recent years by the emergence of the combinatorial library and parallel synthesis strategies whereby the synthesis of vast arrays of molecules incorporating novel amino acids can be readily achieved. 2 An area of notable success in this field has been in the design of peptidomimetics of the Arg-Gly-Asp integrin receptor recognition sequence) Present in an array of endogenous and natural product ligands with affinity for an array of receptors, the RGD sequence has been successfully modified by conformational constraint at each of the amino acid residues in the tripeptide sequence. In particular, inhibition of platelet aggregation by antagonism of the binding of fibrinogen to the platelet membrane receptor glycoprotein IIb/IIIa (GpIIb/IIIa) has been demonstrated and a number of these agents are in clinical trial.4 An important requirement of these constrained peptidomimetics is that they act selectively and avoid interactions with other integrins which may result in severe side effects, s In this regard, a second class of inhibitors has been described based upon the fibrinogen T-chain specific binding domain. 6 Amino acid derivatives of the tropane alkaloid natural products 7 (Figure 1) have been synthesised and evaluated for potential application as peptidomimetics. These molecules contain the structural elements desirable in a peptidomimetic-amino and carbonyl groups held in an relatively rigid orientation by a cyclic structure. The structural diversity within this class of heterocycle allows for a variety of conformational families * Current address: ThrombogenixPty. Ltd., Departmentof Medicine,Monash University,Box Hill Hospital, Arnold St., Box Hill 3128 Australia. email: Phil.Thompson@boxhill.med.monash.edu.au. 0960-894X/98/$ - see front matter © 1998 Published by Elsevier Science Ltd. All rights reserved. PII: S0960-894X(98)00493-4