Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists.
The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC50's = 20 microm) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC50 = 2 nm) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC50 = 980 nm) and estradiol production from primary rat ovarian granulosa cells (EC50 = 10.5 nm). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy.
Affymax, Inc., Palo Alto, California 94304. Electronic address: syanofsky@sbcglobal.net.
Stephen D
SD
Yanofsky
Women's Health and Musculoskeletal Biology, Wyeth Pharmaceuticals, Collegeville, Pennsylvania, 19426-3930.
Emily S
ES
Shen
Affymax, Inc., Palo Alto, California 94304.
Frank
F
Holden
Affymax, Inc., Palo Alto, California 94304.
Erik
E
Whitehorn
Affymax, Inc., Palo Alto, California 94304.
Barbara
B
Aguilar
Affymax, Inc., Palo Alto, California 94304.
Emily
E
Tate
Affymax, Inc., Palo Alto, California 94304.
Christopher P
CP
Holmes
Affymax, Inc., Palo Alto, California 94304.
Randall
R
Scheuerman
Affymax, Inc., Palo Alto, California 94304.
Derek
D
MacLean
Women's Health and Musculoskeletal Biology, Wyeth Pharmaceuticals, Collegeville, Pennsylvania, 19426-3930.
May M
MM
Wu
Women's Health and Musculoskeletal Biology, Wyeth Pharmaceuticals, Collegeville, Pennsylvania, 19426-3930.
Donald E
DE
Frail
Women's Health and Musculoskeletal Biology, Wyeth Pharmaceuticals, Collegeville, Pennsylvania, 19426-3930.
Francisco J
FJ
López
Women's Health and Musculoskeletal Biology, Wyeth Pharmaceuticals, Collegeville, Pennsylvania, 19426-3930.
Richard
R
Winneker
Women's Health and Musculoskeletal Biology, Wyeth Pharmaceuticals, Collegeville, Pennsylvania, 19426-3930.
Brian J
BJ
Arey
Affymax, Inc., Palo Alto, California 94304.
Ronald W
RW
Barrett
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D011962:Receptors, FSH / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology*
D011962:Receptors, FSH; D045162:Thiazolidinediones; D011374:Progesterone; D004958:Estradiol; D005640:Follicle Stimulating Hormone