A Potent, Nonpeptidyl 1<i>H</i>-Quinolone Antagonist for the Gonadotropin-Releasing Hormone Receptor

DeVita, Robert J.; Walsh, Thomas; Young, Jonathan R.; Jiang, Jinlong; Ujjainwalla, Feroze; Toupence, Richard B.; Parikh, Mamta; Huang, Song X.; Fair, Jason A.; Goulet, Mark T.; Wyvratt, Matthew J.; Lo, Jane; Ren, Ning; Yudkovitz, Joel B.; Yang, Yi Tien; Cheng, Kang; Cui, Jisong; Mount, George R.; Rohrer, Susan P.; Schaeffer, James M.; Rhodes, Linda; Drisko, Jennifer E.; McGowan, Erin; MacIntyre, D. Euan; Vincent, Stella; Carlin, J. R.; Cameron, Judy L.; Smith, R. G.

doi:10.1021/jm000275p

Cited by 46 publications

(23 citation statements)

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“…The following chemical structures (collectively referenced as "pharmacoperones") were utilized; those of the quinolone class are prefaced by the letter "Q" and those of the indole class by the letters "IN" and were produced by Merck and Company (Ashton et al, 2001a;Ashton et al, 2001b;Ashton et al, 2001c;DeVita et al, 1999a;DeVita et al, 1999b;DeVita et al, 2001;Walsh et al, 2000): Q89, (7-chloro-2-oxo-4-{2-[(2S)-piperidin-2-yl]ethoxy}-N-pyrimidin-4-yl-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxamide); Q76, (N-(7-chloro-3-(3,5- -chloro-6-[(6,7-dimethoxy-3,4-…”

Section: Methodsmentioning

confidence: 99%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

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SUMMARYAll reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct mis-folding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.

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Section: Methodsmentioning

confidence: 99%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

Self Cite

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“…However, at the rat GnRH receptor a 10-fold lower affinity was found. 26 Compound 8 was also characterized in in vivo studies. Intravenous administration of 3 mg/kg of 8 resulted in 79% suppression of LH and 92% suppression of testosterone blood levels in primates.…”

Section: B Quinolin-2-one Derivativesmentioning

confidence: 99%

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Heitman

IJzerman

2008

Medicinal Research Reviews

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The hypothalamic-pituitary-gonadal (HPG) axis, important in reproduction and sex hormone-dependent diseases, is regulated by a number of G protein-coupled receptors. The recently "deorphanized" GPR54 receptor activated by the peptide metastin is thought to be the key regulator of the axis, mainly by releasing gonadotropin-releasing hormone (GnRH) from the hypothalamus. The latter decapeptide, through the activation of the GnRH receptor in the anterior pituitary, causes the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently activate their respective receptors on the gonadotrope cells. In this review we will discuss the small molecule agonists and antagonists that are currently being developed to intervene with the action of these four receptors. For GnRH receptors, 14 different chemical classes of non-peptidic antagonists have been reported, while for the LH receptor three classes of agonists have been described. Both agonists and antagonists have been introduced for the FSH receptor. Recently, the first non-peptidic agonist for GPR54 was reported.

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“…GnRH agonists and antagonists developed to date are injectable or depot formulations of GnRH peptide analogs (Bouchard, 1996). Although other laboratories have reported active nonpeptide GnRH antagonists (Walsh et al, 2000;Ashton et al, 2001a,b;DeVita et al, 2001;Zhu et al, 2002a,b), few have shown oral activity in animal models (Cho et al, 1998;Besecke et al, 2001;Ashton et al, 2001c). An unmet clinical need still exists for an orally available GnRH receptor antagonist.…”

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confidence: 99%

Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Anderes¹,

Luthin²,

Castillo³

et al. 2003

J Pharmacol Exp Ther

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Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in treating numerous hormone-dependent pathologies including cancers of the prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet clinical need exists for an orally available GnRH receptor antagonist. Guided by structure-activity relationships, ligand-based targeted library designs, and biomarker measurements, our discovery efforts have yielded a novel, small molecule GnRH receptor antagonist, 5- [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8, and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH receptors versus various G-protein-coupled receptors and other enzymes and ion channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a competitive antagonist of GnRHstimulated increases in extracellular acidification rates in Cytosensor microphysiometer assays. In cells expressing recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated total inositol phosphate accumulation. The effects of CMPD1 on circulating levels of luteinizing hormone (LH) and testosterone were studied in castrated and intact male rats, respectively. Intravenous and oral administration of CMPD1 dose dependently suppressed GnRH-mediated elevations of LH in castrated male rats and testosterone in gonadintact male rats. Moreover, CMPD1, when given at 20 mg/kg i.v. to intact male rats, inhibited the elevations of LH and testosterone stimulated by the superagonist of GnRH, [D-Ala 6 , desGly 10 ]GnRH (GnRH-A). These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases.Gonadotropin-releasing hormone (GnRH) is a neuroendocrine decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-ProGly-NH 2 ) synthesized in the neurovascular terminals of the hypothalamus and is secreted in a pulsatile manner directly into the hypophyseal portal blood supply. GnRH selectively binds specific receptors on the membranes of the anterior pituitary gonadotroph cells to stimulate synthesis and release of the gonadotropic hormones [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)]. LH and FSH stimulate gonadal production of sex steroids and gametogenesis, respectively. GnRH, as the primary regulator of LH, is consequently the primary regulator of the sex hormones testosterone and estrogen. GnRH and its analogs have stimulated much interest because of their potential therapeutic benefit in treating sex hormone-dependent diseases such as prostate, ovarian, and breast cancer, as well as endometriosis, uterine fibroids, benign prostate hyperplasia, fertility disorders, and precocious puberty (Huirne and Lambalk, 2001). In contrast to GnRH agonists, which are associated with an initial surge in LH and testosterone ...

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A Potent, Nonpeptidyl 1H-Quinolone Antagonist for the Gonadotropin-Releasing Hormone Receptor

Cited by 46 publications

References 13 publications

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

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