3-[(2<i>R</i>)-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

Fc, Tucci; Zhu, Yan; Rs, Struthers; Z, Guo; Td, Gross; Mw, Rowbottom; Acevedo, Oscar L.; Gao, Yongli; Saunders, John; Xie, Qibing; Gj, Reinhart; Xj, Liu; Ling, Nicholas; Ak, Bonneville; T, Chen; Bozigian, Haig; Chen, C

doi:10.1021/jm049218c

Cited by 53 publications

(44 citation statements)

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“…X-ray analysis of the acetate of 6 revealed that the major atropisomer 6B possessed an aR (M) configuration derived from the fixed R-configuration of the 3-side chain, 11 suggesting that the aR-isomer is more stable in the solid state. The dihedral angle between the 5-phenyl group and the uracil ring is À70.8 (C4 -C5 -C1V -C2V) and À75.3 (C6 -C5 -C1V -C6V) degrees, demonstrating a semiorthogonal relationship of these two aromatic rings.…”

Section: Resultsmentioning

confidence: 99%

“…11 Proton, carbon, and fluorine NMR spectra were acquired on a Varian XL400 spectrometer. Experiments measuring the time course of the atropisomerization were done on a Bruker Avance 500-MHz spectrometer at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…The crystal form of 6 (acetate salt, 5 mg) 11 was dissolved in chloroform-d (0.5 ml), and proton spectra were recorded every 10 min starting at 10 min (t = 0) at 25jC. The relative ratio of the two atropisomers was determined by integration of the 6-proton of the 5-(2-fluoro-3-methoxyphenyl) group of 6.…”

Section: Nmr Analyses Of Enriched Atropisomersmentioning

confidence: 99%

“…1), a potent and orally active gonadotropin-releasing hormone receptor antagonist, has been advanced into clinical evaluation for the treatment of GnRH-related diseases such as endometriosis and uterine fibroids. 11 Although it has only one ''conventional'' chiral center at the 3-side chain derived from R-phenylglycine, the diastereogenicity was unexpectedly observed by NMR analysis. The stereogenic axis arises from the carbon -carbon bond joining the uracil at the 5-position to the quaternary benzenoid carbon atom of the 2-fluoro-3-methoxyphenyl group (Fig.…”

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Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2R)‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil

Tucci

Mesleh

et al. 2005

Chirality

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1-(2,6-Difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (6), a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor, exists as a pair of atropisomers in solution, which was detected by NMR spectroscopy, and separable by HPLC. In addition to a (R)-configured benzylamine, there is a second stereogenic element due to the presence of a chiral axis between the substituted 5-phenyl group and the uracil core. The rate constant of the interconversion (k = 5.07 x 10(-5) s(-1)) of these two atropisomers was determined by proton NMR analysis of a diastereoisomer-enriched sample in aqueous solution at 25 degrees C, and the corresponding Gibbs free energy DeltaG(#) of rotation barrier (97.4 kJ mol(-1)) was calculated using the Eyring equation. The diastereoisomer half-life at physiological temperature (37 degrees C) in aqueous media was estimated to be about 46 min.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Nmr Analyses Of Enriched Atropisomersmentioning

confidence: 99%

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confidence: 99%

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Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2R)‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil

Tucci

Mesleh

et al. 2005

Chirality

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“…TAK-013 entered clinical trials for endometriosis and uterine fibroids in the United States, Europe, and Japan. Researchers from Neurocrine Biosciences developed several new nonpeptide GnRH antagonists, including NBI-42902 (Tucci et al, 2005). Nonpeptide GnRH antagonists offer convenient oral administration, which is particularly important in long-term treatment of GnRH-dependent precocious puberty, endometriosis, and prostate cancer.…”

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confidence: 99%

Challenges and Opportunities of Trapping Ligands

Szkudlinski

2007

Mol Pharmacol

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Because gonadotropin-releasing hormone (GnRH) analogs constitute an important class of therapeutics for various reproductive and hormone-dependent disorders, many novel compounds have been discovered and studied. Several orally active nonpeptide GnRH antagonists have recently gained increased attention. In the study published in this issue of Molecular Pharmacology, Kohout et al. (p. 238) used smallmolecule TAK-013 (sufugolix; developed previously by Takeda Chemical Industries) as a tool to elucidate the mechanism of its insurmountable antagonism. On the basis of receptor mutagenesis combined with molecular modeling, the authors hypothesized that certain amino acid sequences uniquely present in the human GnRH receptor amino terminus and extracellular loop 2 may form a "trap door" retarding dissociation of TAK-013. Such a trapping mechanism could be both ligand-and receptor species-specific. Although analogous models were previously proposed for other G protein-coupled receptors, the study by Kohout et al. (2007) provides an important advance in the GnRH antagonists field and an illustration of the fact that preclinical studies using animal models with nonhuman receptors may have very limited value in predicting drug efficacy in human disease. There are many examples showing that highaffinity protein, peptide, or nonpeptide agonists or antagonists have also enhanced clinical efficacy. However, there are also numerous studies indicating that very high receptor binding affinity is not a guarantee of drug efficacy and that other factors, including pharmacokinetic profile, ligand-induced receptor desensitization, and "trafficking," are critical in design and development of optimal drugs.Gonadotropin-releasing hormone (GnRH) is a polypeptide produced in specialized neurons of the hypothalamus. GnRH is released in pulses into the hypophyseal portal system, reaches the anterior pituitary, and stimulates synthesis and secretion of two gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH receptor is a member of G protein-coupled receptor superfamily with seven cell membrane-spanning helices. The human GnRH receptor preferentially binds GnRH I and couples to G q/11 protein in pituitary cells, leading to the stimulation of phospholipase C and calcium mobilization (Hazum and Conn, 1988;Millar, 2005). GnRH I is more potent in the activation of the G q/11 protein in the gonadotrope; however, GnRH II is more potent in the stimulation of apoptosis and antiproliferative effects through activating G i protein-mediated signaling. GnRH binding also causes up-regulation and clustering of GnRH receptors, resulting in their internalization, partial degradation, and recycling. Activation of many GPCR receptors, including GnRH receptor, is likely to be associated with breaking, by a ligand, the intrareceptor interactions that stabilize the receptor in its inactive conformations, creating new inter-and intramolecular contacts, resulting in ligandspecific set of receptor conformations (Zhang et al.,...

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Chirality and Biological Activity

Singh¹,

Hagen²

2010

Burger's Medicinal Chemistry and Drug Discovery

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The relationship between chirality and biological activity has been of increasing importance to the pharmaceutical and biopharmaceutical areas as evidenced by a growing number of chiral drugs that have been developed within the last two decades. This chapter covers several areas of importance in the design and synthesis of novel small molecule chiral drugs for medicinal chemists. The focus of this chapter is to provide an overview of the impact of chirality in medicinal chemistry and pharmaceutical sciences, and this should not be considered an exhaustive review of the topic. Several examples reported in the recent literature have been used to highlight the impact of chirality on development of therapeutics for various molecular targets. Chirality, as used in this chapter, also includes examples of atropisomers. The effects of chirality on pharmacological activities, absorption, distribution, metabolism, and excretion and toxicity are exemplified. In addition to chirality at carbon, examples of chiral compounds involving chirality at noncarbon atoms are included. A section on chirality in drug design provides several examples from recent literature covering diverse target classes. Regulatory considerations that apply to chiral drugs are addressed briefly. Section 10 covers recent drug development and marketed single enantiomers. Multiple synthetic approaches to produce chiral compounds with high enantiomeric purity, including chromatographic separation and enantioselective syntheses, were covered adequately in the 6th edition, and thus these areas and general definitions of chirality are not repeated in this chapter.

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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

Cited by 53 publications

References 28 publications

Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2R)‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil

Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2R)‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil

Challenges and Opportunities of Trapping Ligands

Chirality and Biological Activity

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