Discovery of a novel, orally active, small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist.
Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).
Li
Haitao
H
Department of Medicinal Chemistry, Research Pharmacology, and Pharmacokenetics, Dynamics & Metabolism, Pfizer Global Research & Development, 10770 Science Center Drive, San Diego, California 92121, USA. haitao.li@pfizer.com
Anderes
Kenna L
KL
Kraynov
Eugenia A
EA
Luthin
David R
DR
Do
Quyen-Quyen
QQ
Hong
Yufeng
Y
Tompkins
Eileen
E
Sun
Eric T
ET
Rajapakse
Ranjan
R
Pathak
Ved P
VP
Christie
Lance C
LC
Feng
Jun
J
Vazir
Haresh
H
Castillo
Rosemary
R
Gregory
Margaret L
ML
Castro
Mary
M
Nared-Hood
Karen
K
Paderes
Genevieve
G
Anderson
Mark B
MB
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis; D008297:Male; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009919:Orchiectomy; D010902:Pituitary Gland / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000378:metabolism
D007192:Indenes; D007295:Inositol Phosphates; D009025:Morpholines; C511638:N-(4,6-dimethoxy-2-((3-morpholin-4-ylpropyl)amino)pyrimidin-5-yl)-5-(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yloxy)-2-furamide; D011743:Pyrimidines; D011966:Receptors, LHRH; D011994:Recombinant Proteins; D013739:Testosterone