Donald Bierer

Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity

The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.

New β-glucan inhibitors as antifungal drugs

Introduction: New classes of synthetic and semi-synthetic β-glucan inhibitors have recently emerged, providing analogs that, in some cases, have been proven to have a high degree of activity against fungi, offering the prospect of alternatives to the commercially available lipopeptide/echinocandin agents caspofungin, micafungin and anidulafungin. Area covered: This review covers applications disclosing compound classes that include synthetic pyridazinone analogs, bicyclic heteroaryl ring compounds, aniline derivates, and semi-synthetic echinocandin and enfumafungin derivatives. MK-3118 is an analog of the natural product enfumafungin that, in particular, shows promise as it has a spectrum of activity comparable with caspofungin but has the advantageous property of oral bioavailability. Expert opinion: The diversity of chemical classes in the present review, which have demonstrable activity against β-glucan and the prospect of oral bioavailability, offers hope that safe and effective antifungal drugs will emerge and be commercialized. Of particular note, the Merck compound MK-3118, with solid evidence of efficacy based on preclinical data, has moved into clinical trials.

Development of Potent and Metabolically Stable APJ Ligands with High Therapeutic Potential

The apelin ligand receptor system is an important target to develop treatment strategies for cardiovascular diseases. Although apelin exhibits strong inotropic effects, its pharmaceutical application is limited because no agonist with suitable properties is available. On the one hand, peptide ligands are too instable, and on the other hand, small‐molecule agonists show only low potency. This study describes the development of apelin (APJ) receptor agonists with not only high activity but also metabolic stability. Several strategies including capping of termini, insertion of unnatural amino acids, cyclization, and lipidation were analyzed. Peptide activity was tested using a Ca2+‐mobilization assay and the degradation of selected analogues was analyzed in rat plasma. The best results were obtained by N‐terminal lipidation of a 13‐mer apelin derivative. This analogue displayed a half‐life of 29 h in rat plasma, compared with 0.025 h for the wild‐type peptide. Furthermore, in vivo pharmacokinetics revealed a clearance of 0.049 L h−1 kg−1 and a half‐life of 0.36 h. In summary, amino acid substitution and fatty acid modification resulted in a potent and 1000‐fold more stable peptide that exhibits high pharmaceutical potential.

Nickel Phosphite/Phosphine-Catalyzed C–S Cross-Coupling of Aryl Chlorides and Thiols

A method for the coupling of aryl chlorides and thiophenols using an air-stable nickel(0) catalyst is described. This thioetherification procedure can be effectively applied to a range of electronically diverse aryl/heteroaryl chlorides without more expensive metal catalysts such as palladium, iridium, or ruthenium. This investigation also illustrates both, a variety of thiol coupling partners and, in certain cases, the use of Cs2CO3.

Synthesis of Peptide Disulfide-Bond Mimics by Using Fully Orthogonally Protected Diaminodiacids

A new strategy was developed for the synthesis of peptide disulfide-bond mimics using fully orthogonally protected diaminodiacids. This method overcomes the previous problems of heavy-metal contamination and poor compatibility with Fmoc chemistry and provides a practical avenue for the efficient preparation of peptide disulfide-bond mimics.

The Impact of Adrenomedullin Thr22 on Selectivity within the Calcitonin Receptor-like Receptor/Receptor Activity-Modifying Protein System

Adrenomedullin (ADM) is a peptide hormone of the calcitonin gene‐related peptide (CGRP) family. It is involved in the regulation of cardiovascular processes such as angiogenesis, vasodilation, and the reduction of oxidative stress. ADM mediates its effects by activation of the ADM‐1 and ‐2 receptors (AM1R/AM2R), but also activates the CGRP receptor (CGRPR) with reduced potency. It binds to the extracellular domains of the receptors with its C‐terminal binding motif (residues 41–52). The activation motif, consisting of a disulfide‐bonded ring structure (residues 16–21) and an adjacent helix (residues 22–30), binds to the transmembrane region and stabilizes the receptor conformation in the active state. While it was shown that the binding motif of ADM guides AM1R selectivity, there is little information on the activation motif itself. Here, we demonstrate that Thr22 of ADM contributes to the selectivity. By using solid‐phase peptide synthesis and cAMP‐based signal transduction, we studied the effects of analogues in the activation motif of ADM on AM1R and CGRPR activity. Our results indicate that Thr22 terminates the α‐helix and orients the ring segment by hydrogen bonding. Using olefin stapling, we showed that the α‐helical arrangement of the ring segment leads to decreased AM1R activity, but does not affect CGRPR activation. These results demonstrate that the conformation of the ring segment of ADM has a strong impact on the selectivity within the receptor system.