Author: Lutz S. Richter ; Gianine M. Figliozzi ; Erin K. Bradley ; Dane A. Goff ; Ronald N. Zuckermann ; Jeffrey M. Blaney ; David C. Spellmeyer ; Janice M. Kerr

Synthesis and screening of combinatorial libraries for pharmaceutical lead discovery is a rapidly expanding field. Oligo-N-substituted glycines (NSGs) were one of the earliest sources of molecular diversity in combinatorial libraries. In one of the first demonstrations of the power of combinatorial chemistry, two NSG trimers, CHIR-2279 and CHIR-4531, were identified as nM ligands for two 7-transmembrane G-protein-coupled receptors. The NMR characterization of these two lead compounds was undertaken to verify covalent connectivity and to determine solution conformations, if any. The sequential chemical shift assignments were performed using a new strategy for assigning 1H and 13C resonances of NSGs. The conformational preferences were then determined in both an aqueous co-solvent system and an organic solvent to probe the effects of hydrophobic collapse. NSGs are expected to be more flexible than peptides due to the tertiary amide, with both cis and trans amide bond conformations being accessible. Solution NMR studies indicate that although CHIR-2279 and CHIR-4531 have identical backbones and termini, and very similar side chains, they do not display the same solution conformational characteristics.

19 Aug 1994·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Nanomolar Ligands for 7-Transmembrane G-Protein-Coupled Receptors from a Diverse N-(Substituted)glycine Peptoid Library

Q1 · MEDICINE

Article

Author: Siani, Michael A. ; Shoemaker, Kevin R. ; Simon, Reyna ; Kerr, Janice M. ; Wang, Liang ; Martin, Eric J. ; Moos, Walter H. ; Goff, Dane A. ; Stauber, Gregory B. ; Figliozzi, Gianine M. ; Spellmeyer, David C. ; Zuckermann, Ronald N. ; Banville, Steven C. ; Brown, Edward G. ; Richter, Lutz S.

Screening a diverse, combinatorial library of ca. 5000 synthetic dimer and trimer N-(substituted)glycine "peptides" yielded novel, high-affinity ligands for 7-transmembrane G-protein-coupled receptors. The peptoid library was efficiently assembled using readily available chemical building blocks. The choice of side chains was biased to resemble known ligands to 7-transmembrane G-protein-coupled receptors. All peptides were screened in solution-phase, competitive radioligand-binding assays. Peptoid trimer CHIR 2279 binds to the alpha 1-adrenergic receptor with a Ki of 5 nM, and trimer CHIR 4531 binds to the mu-opiate receptor with a Ki of 6 nM. This represents the first example of the discovery of high-affinity receptor ligands from a combinatorial library of non-natural chemical entities.

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Indication	Highest Phase	Country/Location	Organization	Date
Pain	Phase 3	US	Chiron Corp.	-
Gastrointestinal Diseases	Discovery	US	Chiron Corp.	-

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