Jürgen Boer

Discovery and Evaluation of a Non-Zn Chelating, Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitor for Potential Intra-articular Treatment of Osteoarthritis

Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.

Cellular solid-phase binding assay and mass spectrometry for screening of α4β7 integrin antagonists

Abstract A qualitative cellular solid-phase binding assay for screening α4β7 integrin antagonists attached via photolinker to TentaGel® Macrobeads has been developed. An activation of the integrins with Mn 2+ was necessary to achieve binding to the bead bound antagonists. The identification of the resin bound compounds was done by mass spectrometry.

Synthesis and NMR Structure of Peptidomimetic α4β7-Integrin Antagonists

The development of new anti-inflammatory drugs is currently one of the great challenges in medicinal chemistry. Recently, 4 1and 4 7 integrins were shown to be promising targets for treating inflammatory and autoimmune diseases. 4 7 integrins bind to the mucosal addressin cell adhesion molecule 1 (MAdCAM-1) through their Leu-Asp-Thr sequence (LDT sequence) specifically and with high affinity. 6] An overexpression of MAdCAM-1 occurs in mouse models of colitis, in human inflammatory bowel disease (IBD), and in chronic inflammatory liver disease. 8] Recently, we and others were able to derive peptidic 4 7 integrin antagonists from the natural LDT-binding sequence. For the further development of nonpeptidic and highly selective drugs, we identified the structural and functional requirements of the LDT recognition sequence within 4 7 integrin antagonists by using several peptidomimetic variations such as peptoids, azapeptides, and reduced amide bonds (Scheme 1). An aromatic residue N-terminal to the LDTsequence

β-D-Mannose Based Peptidomimetics in the Design of α4ß1 and α4β7 Antagonists

Interfering protein-protein interaction by small non-peptidic molecules is one of the great challenges in medicinal chemistry. The use of rigid scaffolds to generate peptidomimetics was first proposed by Fanner [1]. Carbohydrate moieties as scaffolds were first introduced by Hirschmann and Nicolaou [2].

Peptidic Inhibitors for Protein-Protein Interactions at Cell Surfaces

Interactions at cell surfaces are involved in a number of regulatory functions in living systems and therefore represent interesting drug targets such as the development of cyclic peptides and peptidomimetics of the RGD sequence [1]. Here we present two further examples diminishing a protein sequence into cyclic peptides with improved affinity, selectivity and enhanced proteolytic stability.