Discovery and optimization of (R)-prolinol-derived agonists of the Growth Hormone Secretagogue receptor (GHSR).
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.
Zhai
Weixu
W
Bristol Myers Squibb Co., Early Discovery Chemistry, Wallingford, CT 06492, USA.
Flynn
Neil
N
Longhi
Daniel A
DA
Tino
Joseph A
JA
Murphy
Brian J
BJ
Slusarchyk
Dorothy
D
Gordon
David A
DA
Pendri
Anna
A
Shi
Shuhao
S
Stoffel
Robert
R
Ma
Baoqing
B
Sofia
Michael J
MJ
Gerritz
Samuel W
SW
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
D011759:Pyrrolidines; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C010509:prolinol