title: Discovery and optimization of (R)-prolinol-derived agonists of the Growth Hormone Secretagogue receptor (GHSR).
abstract: 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 alpha-methyl stereochemistry of the phenoxyacetamide sidechain on GHSR activity.
authors: Bristol Myers Squibb Co., Early Discovery Chemistry, Wallingford, CT 06492, USA.
authors: Weixu
authors: W
authors: Zhai
authors: Neil
authors: N
authors: Flynn
authors: Daniel A
authors: DA
authors: Longhi
authors: Joseph A
authors: JA
authors: Tino
authors: Brian J
authors: BJ
authors: Murphy
authors: Dorothy
authors: D
authors: Slusarchyk
authors: David A
authors: DA
authors: Gordon
authors: Anna
authors: A
authors: Pendri
authors: Shuhao
authors: S
authors: Shi
authors: Robert
authors: R
authors: Stoffel
authors: Baoqing
authors: B
authors: Ma
authors: Michael J
authors: MJ
authors: Sofia
authors: Samuel W
authors: SW
authors: Gerritz
mesh_terms: D020650:Combinatorial Chemistry Techniques; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D054440:Receptors, Ghrelin / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011759:Pyrrolidines; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C010509:prolinol