Journal article
Discovery and optimization of ( R)-prolinol-derived agonists of the Growth Hormone Secretagogue receptor (GHSR)
Bioorganic & medicinal chemistry letters, v 18(18), pp 5083-5086
15 Sep 2008
PMID: 18722770
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The discovery of single-digit nanomolar full agonists (e.g.,
10b) of the Growth Hormone Secretagogue receptor (GHSR) is reported, starting with a micromolar screening hit identified from a GPCR-targeted solid-phase library. The ‘library pedigree’ of this series greatly facilitated its rapid optimization.
The discovery and optimization of a novel series of prolinol-derived GHSR agonists is described. This series emerged from a 11,520-member solid-phase library targeting the GPCR protein superfamily, and the rapid optimization of low micromolar hits into single-digit nanomolar leads can be attributed to the solid-phase synthesis of matrix libraries, which revealed multiple non-additive structure–activity relationships. In addition, the separation of potent diastereomers highlighted the influence of the α-methyl stereochemistry of the phenoxyacetamide sidechain on GHSR activity.
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Details
- Title
- Discovery and optimization of ( R)-prolinol-derived agonists of the Growth Hormone Secretagogue receptor (GHSR)
- Creators
- Weixu Zhai - Bristol-Myers Squibb (United States)Neil Flynn - Bristol-Myers Squibb (United States)Daniel A. Longhi - Bristol-Myers Squibb (United States)Joseph A. Tino - Bristol-Myers Squibb (Germany)Brian J. Murphy - Bristol-Myers Squibb (United States)Dorothy Slusarchyk - Bristol-Myers Squibb (United States)David A. Gordon - Bristol-Myers Squibb (United States)Anna Pendri - Bristol-Myers Squibb (United States)Shuhao Shi - Bristol-Myers Squibb (United States)Robert Stoffel - Bristol-Myers Squibb (United States)Baoqing Ma - Bristol Myers Squibb Co., Analytical R&D, Wallingford, CT 06492, USAMichael J. Sofia - Bristol-Myers Squibb (United States)Samuel W. Gerritz - Bristol-Myers Squibb (United States)
- Publication Details
- Bioorganic & medicinal chemistry letters, v 18(18), pp 5083-5086
- Publisher
- Elsevier
- Number of pages
- 4
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Pharmacology and Physiology
- Web of Science ID
- WOS:000259149400037
- Scopus ID
- 2-s2.0-51549088989
- Other Identifier
- 991021902528904721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Organic