organic chemistry, review organic chemistry, review Z 0200 29 -294 The Unique Properties of Dipeptidyl-Peptidase IV (DPP IV / CD26) and the Therapeutic Potential of DPP IV Inhibitors -[154 refs.]. -(AUGUSTYNS, K.; BAL, G.; THONUS, G.; BELYAEV, A.; ZHANG, X. M.; BOLLAERT, W.; LAMBEIR, A. M.; DURINX, C.; GOOSSENS, F.; HAEMERS, A.; Curr. Med. Chem. 6 (1999) 4, 311-327; Dep. Pharm. Chem., Univ. Antwerp, B-2610 Wilrijk, Belg.; EN)

Vildagliptin is a marketed DPP4 inhibitor, used in the management of type 2 diabetes. The molecule also has notable DPP8/9 affinity, with some preference for DPP9. Therefore, we aimed to use vildagliptin as a starting point for selective DPP8/9 inhibitors, and to engineer out the parent compound's DPP4affinity. In addition, we wanted to identify substructures in the obtained molecules that allow their further optimization into inhibitors with maximal DPP9 selectivity. Various 2S-cyanopyrrolidines and isoindoline were investigated as P1 residues of vildagliptin analogs. The obtained set was expanded with derivatives bearing O-substituted, N-(3-hydroxyadamantyl)glycine moieties at the P2 position. In this way, representatives were discovered with DPP8/9 potencies comparable to the parent molecule, but with overall selectivity towards DPP4, DPP2, FAP, and PREP. Furthermore, the most promising molecules in this series have a 4-to 7-fold preference for DPP9 over DPP8. Finally, a molecular dynamics study was carried out to maximize our insight into experimental selectivity data.

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This review deals with the properties and functions of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). This membrane anchored ecto-protease has been identified as the leukocyte antigen CD26. The following aspects of DPP IV/CD26 will be discussed: the structure of DPP IV and the new family of serine proteases to which it belongs, the substrate specificity, the distribu­tion in the human body, specific DPP IV inhibitors and the role of CD26 in the intestinal and renal handling of proline containing peptides, in cell adhesion, in peptide metabolism, in the immune system and in HIV infection. Especially the latest developments in the search for new inhibitors will be reported as well as the discovery of new natural substrates for DPP IV such as the glucagon-like peptides and the chemokines. Finally the therapeutical perspectives for DPP IV inhibitors will be discussed.

l-(2.3-dideoxy-p-D-erythro-hexopyranosyl)thymine was used at several positions as nucleoside substitute in the synthesis of oligonucleotides using the H-phosphonate chemistry. A 13-mer with one hexose nucleoside substitution at each end had equivalent hybridization properties as compared to the non-modified 13-mer. However, addition of a second analogue at each end or modification in the middle of a 13-mer caused a sharp decrease in melting temperature. Substitution at the 3'-end with two nucleoside analogues was necessary to withstand the action of snake venom phosphodiesterase.