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3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2005 Feb 24; Vol. 48 (4), pp. 1169-78. - Publication Year :
- 2005
-
Abstract
- Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (K(i) = 0.56 nM) and was a potent functional antagonist (IC(50) = 3.0 nM in Ca(2+) flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (K(i) = 3.9 nM). In addition, R-13bhad good plasma exposure in cynomolgus monkeys after oral administration, with a C(max) of 737 ng/mL and an AUC of 2392 ng/mL.h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.
- Subjects :
- Administration, Oral
Animals
Biological Availability
Crystallography, X-Ray
Drug Design
Humans
In Vitro Techniques
Macaca fascicularis
Male
Membranes drug effects
Membranes metabolism
Molecular Structure
Orchiectomy
Pituitary Gland drug effects
Pituitary Gland metabolism
Rats
Species Specificity
Stereoisomerism
Structure-Activity Relationship
Thymine chemistry
Thymine pharmacology
Receptors, LHRH antagonists & inhibitors
Thymine analogs & derivatives
Thymine chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 48
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15715483
- Full Text :
- https://doi.org/10.1021/jm049218c