The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
Our results indicate that the combination of VNN1 and MMP9 may be used as a novel blood biomarker panel for the discrimination of pancreatic cancer-associated diabetes from type 2 diabetes.
Corticosteroids are not detrimental to DILI, but instead ameliorate liver injury and improve patient survival. Short-time use of corticosteroids is strongly recommended for severe DILI patients with hyperbilirubinemia.
Insulin-like growth factors (IGF-I and II) play an important role in metabolic and mitogenic activities through stimulation of the IGF-I receptor on the cell surface. Although the concentration of IGF in blood and cerebrospinal fluid is quite high (>100 nM), this large pool of IGF is biologically inactive because of its association with six distinct binding proteins, which form high-affinity complexes with IGF. Thus, inhibitors of IGF-binding proteins (IGFBPs), especially IGFBP-3, could potentially alter the distribution between the "free" and "bound" forms of IGF and thereby elevate biologically active IGF-I to exert a beneficial effect on those patients with diseases that respond to the application of exogenous IGF-I. Whereas IGF-I peptide variants, which bind to IGFBPs but not the IGF-I receptor, have been shown to be potent IGF/IGFBP inhibitors, small molecule nonpeptide IGF/IGFBP inhibitors have the potential advantages of oral bioavailability and flexible dosing regimen. Here we report the discovery of several isoquinoline analogues, exemplified by 1 and 2, which bind IGFBP-3 as well as other IGFBPs at low nanomolar concentrations. More importantly, both compounds were shown to be able to release biologically active IGF-I from the IGF-I/IGFBP-3 complex. These results point to the feasibility of developing orally active therapeutics to treat IGF-responsive diseases by optimization of the lead molecules 1 and 2.
Efforts to develop orally available gonadotropin-releasing hormone (GnRH) receptor antagonists have led to the discovery of several classes of potent nonpeptide antagonists. Here we investigated molecular interactions of three classes of nonpeptide antagonists with human, rat, and macaque GnRH receptors. Although all are high affinity ligands of the human receptor (K i <5 nM), these compounds show reduced affinity for the macaque receptor and bind only weakly (K i >1 M) to the rat receptor. To identify residues responsible for this selectivity, a series of chimeric receptors and mutant receptors was constructed and evaluated for nonpeptide binding. Surprisingly, 4 key residues located in the amino terminus (Met-24) and extracellular loops II (Ser-203, Gln-208) and III (Leu-300) of the GnRH receptor appear to be primarily responsible for species-selective binding. Comparisons of reciprocal mutations suggest that these may not be direct contacts but rather may be involved in organizing extracellular portions of the receptor. These data are novel because most previous reports of residues involved in binding of nonpeptide ligands to peptide-activated G protein-coupled receptors, including the GnRH receptor as well as mono-amine receptors, have identified binding sites in the transmembrane regions.
Gonadotropin-releasing hormone (GnRH)1 is a linear decapeptide amide, pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 , that regulates the reproductive endocrine axis in both male and female vertebrates (1, 2). The GnRH receptor (Gn-RHR) is a member of the G protein-coupled receptor superfamily (3). Its activation stimulates phospholipase C and phosphatidyl inositol turnover by coupling to the GTP-binding proteins G q and G 11 (4). Stimulation of pituitary GnRH receptors by hypothalamic GnRH released into the pituitary portal circulation results in secretion of the gonadotropins, luteinizing hormone, and follicle-stimulating hormone into the peripheral circulation. The gonadotropins in turn regulate the production of steroids and gametes by the gonads. Receptors for GnRH have been cloned from a wide range of species (5), and numerous studies have been reported elucidating key residues in the receptor responsible for peptide binding and signal transduction (5).Peptide drugs that inhibit the action of GnRH have proven useful in regulating the hypothalamic-pituitary-gonadal axis and are now routinely used for ablation of gonadal steroids. This approach has proven effective in the management of endometriosis, prostate cancer, uterine fibroids, breast cancer, and other conditions, including infertility (6). However, the requirement for daily injection or implantation of long acting depots has prompted a number of groups to attempt to develop orally active, nonpeptide antagonists (for a review, see Ref. 7). These efforts have been hindered in part by the species selectivity that is observed for most nonpeptide GnRH antagonists. Cho et al. (8) reported synthesis of T-98475, a nonpeptide GnRH antagonist with high affinity to the hu...
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