Agonists of the follicle stimulating hormone receptor from an encoded thiazolidinone library.
The design, synthesis, characterization, and screening of a large, encoded thiazolidinone library are described. Three sets of 35 building blocks were combined by encoded split-pool synthesis to give a library containing more than 42 000 members. Building block selection was based in part on a novel small molecule follicle stimulating hormone receptor agonist hit and in part for diversity. HPLC/MS techniques were applied at the single-bead level to build confidence in the reliability of library construction. Application of two distinct screening strategies resulted in the identification of compounds with significantly improved potency over the initial hit. This work demonstrates the versatility of encoded libraries for preparing a large number of analogues of a given hit while simultaneously generating a large collection of compounds for screening against other targets.
Maclean
Derek
D
Affymax Research Institute, 4001 Miranda Avenue, Palo Alto, CA 94304, USA. derek.maclean@kaipharma.com
Holden
Frank
F
Davis
Ann M
AM
Scheuerman
Randall A
RA
Yanofsky
Stephen
S
Holmes
Christopher P
CP
Fitch
William L
WL
Tsutsui
Ken
K
Barrett
Ronald W
RW
Gallop
Mark A
MA
D000447:Aldehydes / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D062365:Aminobenzoates / Q000138:chemical synthesis; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D015195:Drug Design; D008156:Luciferases / Q000737:chemistry; D013058:Mass Spectrometry; D015394:Molecular Structure; D011137:Polystyrenes; D011962:Receptors, FSH / Q000819:agonists*; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis*
D000447:Aldehydes; D000596:Amino Acids; D062365:Aminobenzoates; D011137:Polystyrenes; D011962:Receptors, FSH; D013844:Thiazoles; C101297:Tentagel resin; C049654:2-amino-3-methylbenzoic acid; D008156:Luciferases