Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor.
BACKGROUND
In assisted reproductive technology, human chorionic gonadotrophin (hCG) is administered subcutaneously for the induction of oocyte maturation and ovulation. Our efforts to develop orally bioavailable luteinizing hormone (LH) receptor agonists have led to the discovery of Org 43553, a low molecular weight (LMW) LH receptor (LH-R) agonist.


METHODS
Org 43553 was tested in vitro and in vivo in pre-clinical pharmacological models to demonstrate efficacy and oral availability.


RESULTS
Org 43553 is a potent stimulator of the human LH-R in vitro (EC(50) 3.7 nM). In primary mouse Leydig cells, Org 43553 stimulated testosterone production. Pharmacokinetic analyses showed high oral bioavailability in rats (79%) and dogs (44%) with a shorter half-life compared with hCG (3.4 versus 5.6 h in the rat). Ovulation induction by Org 43553 was demonstrated in immature mice as well as in cyclic rats after single-dose oral administration (50 mg/kg). The ovulated oocytes were of good quality as demonstrated by successful fertilization and implantation of normal embryos. In male rats, testosterone production was substantially induced after oral administration.


CONCLUSIONS
Org 43553 is the first LMW LH-R mimetic with demonstrated in vivo efficacy upon oral administration and could therefore replace subcutaneously administered hCG. The elimination half-life of Org 43553 is substantially shorter than hCG, which could potentially represent a clinical benefit in reducing the risk of ovarian hyperstimulation syndrome (OHSS).
van de Lagemaat
R
R
Department of Pharmacology, Medicinal Chemistry, Molecular Design and Informatics, Molecular Pharmacology and Clinical Research, Schering-Plough Research Institute, PO Box 20, 5340 BH Oss, The Netherlands. ruud.vandelagemaat@spcorp.com
Timmers
C M
CM
Kelder
J
J
van Koppen
C
C
Mosselman
S
S
Hanssen
R G J M
RG
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D006063:Chorionic Gonadotropin / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D007985:Leydig Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008970:Molecular Weight; D016471:Ovarian Hyperstimulation Syndrome; D010060:Ovulation / Q000187:drug effects*; D010062:Ovulation Induction; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011974:Receptors, LH / Q000378:metabolism*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
C526583:5-amino-2-methylsulfanyl-4-(3-(2-morpholin-4-ylacetylamino)phenyl)thieno(2,3-d)pyrimidine-6-carboxylic acid tert-butylamide; D006063:Chorionic Gonadotropin; D011743:Pyrimidines; D011974:Receptors, LH; D013876:Thiophenes