Discovery and optimization of novel antagonists to the human neurokinin-3 receptor for the treatment of sex-hormone disorders (Part I).
Neurokinin-3 receptor (NK3R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK3R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma luteinizing hormone (LH) and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK3R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogues to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models.
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Hamid R
HR
Hoveyda
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Graeme L
GL
Fraser
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Marie-Odile
MO
Roy
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Guillaume
G
Dutheuil
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Frédéric
F
Batt
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Mohamed
M
El Bousmaqui
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Julien
J
Korac
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
François
F
Lenoir
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Alexey
A
Lapin
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Sophie
S
Noël
Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.
Sébastien
S
Blanc
D000728:Androgens / Q000097:blood; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003412:Cricetulus; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D004700:Endocrine System Diseases / Q000097:blood / Q000188:drug therapy; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008024:Ligands; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D017207:Rats, Sprague-Dawley; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship
D000728:Androgens; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D018042:Receptors, Neurokinin-3; D007986:Luteinizing Hormone