Klaus Weigand

Microwave-assisted Pd(0)-catalyzed amination of aryl halides on solid support

In this study, the microwave-assisted Pd(0)-catalyzed coupling of aryl halides to Rink resins is compared to a conventional heating protocol. While yields and purities of the coupling products were comparable under both conditions, microwave heating allows a significant acceleration of the reaction. The coupling of electron-deficient aryl halides proceeded within 10–15 minutes, while under conventional conditions 20 h of heating were necessary for complete conversion.

Conformationally Constrained Mimics of the Membrane-Proximal Domain of FcεRIα

The response to an allergen is initiated by the interaction of allergen-specific immunoglobulin E (IgE) with its high affinity receptor FceRI, which is expressed on the surface of mast cells and basophils. Allergen-mediated cross-linking of FceRI-bound IgE initiates receptor aggregation and subsequent cell activation. This results in the release of vasoactive and bronchoconstrictive mediators that trigger the clinical symptoms of type I hypersensitivity. The mouse IgG1/k monoclonal antibody (mAb) 5H5F8 recognizes a linear peptide sequence (KAPR ACHTUNGTRENNUNGKYWL) within the membrane-proximal extracellular region of the human high affinity IgE receptor a-chain (ecFceRIa). Antibody 5H5F8 and its Fab fragment have been shown to block IgE-mediated activation of human basophils without affecting the interaction of IgE with FceRI. The 5H5F8 epitope or “stalk region” has thus been implicated in FceRIa-dependent cell activation. For the design of small molecules that display similar cellular effects as 5H5F8, and which could potentially be developed into new treatments for IgE-mediated allergic conditions, we became interested in the 3D structure of KAPREKYWL. NMR spectroscopy studies, not surprisingly, revealed that the KAPREKYWL peptide has no distinct secondary structure in aqueous solution, and is therefore not suitable for interaction studies with potential small ligands. Thus, we considered synthetic, constrained KAPREKYWL mimics, in which the backbone and side chains adopt a similar conformation as in the native cellular environment, to be suitable tools. Crystal structures of ecFceRIa alone and in complex with an IgE Fc fragment have been determined, but no structural information for the stalk region was provided in these studies. A crystal structure of KAPREKYWL in complex with the Fab fragment of 5H5F8 was therefore used as starting point for the design of such peptide mimics; this approach assumes that this 3D structure represents a good approximation of the conformation on the cell surface. Based on analysis of this structure, we anticipated that the conformation of the nonapeptide in complex with 5H5F8 could be mimicked by introducing an alkylor alkenyl bridge between Ala172 or Pro173, and Lys176. This approach offers the advantage of fine tuning by variation of the chain length. For the synthesis of these peptide mimics we decided to apply ring-closing metathesis (RCM) chemistry. Based on the pioneering work of Grubbs et al. several examples of the ACHTUNGTRENNUNGsynthesis of peptidic macrocycles have been published. The RCM approach has also been used for the stabilization of other preformed secondary-structure motifs, like a helices, or for the synthesis of disulfide mimics. In this communication we describe the design, in silico evaluation and selection of peptidomimetics, their synthesis by RCM, as well as their initial evaluation by binding studies to 5H5F8. Analysis of the X-ray structure of the Fab fragment of 5H5F8 in complex with KAPREKYWL revealed that the peptide binds in an irregular (or “random coil”) conformation, with Arg174, Glu175, and Tyr177 buried in the antigen-binding site. It is worth noting that the side chains of Arg174 and Glu175 formed a tight intramolecular salt bridge. This salt bridge and the orientation of the side chain of Tyr177 squeezed the peptide into a shape in which the main chain dihedral angles of Arg174 and Tyr177 were within the (right-handed) alpha-helical region (approximately F= 608, Y = 508), while all other ACHTUNGTRENNUNGresidues adopted a more extended conformation (Figure 1, Table 1).

Scope and applicability of an expedient synthesis leading to polysubstituted 3-(carboxyphenyl)pyrroles

Abstract A convenient three‐step route toward a functionalized pyrrole building block for novel anti‐inflammatory agents is reported. In contrast to previous strategies, the present approach focuses on inexpensive starting materials and application on a multigram scale. A high degree of functional diversity is demonstrated in various derivatives, and the scope and limitations of this route are discussed. Complementary to the described tetrasubstituted pyrroles, a novel ring‐closure protocol based on the Feist–Benary condensation affords trisubstituted analogues.

Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis

A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.