Identification of 1-Arylmethyl-3- (2-aminoethyl)-5-aryluracil as Novel Gonadotropin-Releasing Hormone Receptor Antagonists

Zhu, Yunfei; Gross, Timothy D.; Connors, Patrick J.; Gao, Yinghong; Tucci, Fábio C.; Struthers, R. Scott; Reinhart, Greg J.; Saunders, John; Chen, Ta Kung; Bonneville, and Anne L. Killam; Chen, Chen

doi:10.1021/jm034041s

Cited by 25 publications

(19 citation statements)

References 7 publications

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“…The cyano-or imidazole-nitrogen was replaced by a carbonyl moiety resulting in pyrimidine-2,4-dione derivatives, which were also referred to as uracil-based GnRH receptor antagonists (Table VIII). 51 Similar substituents as on the previous scaffolds resulted in a GnRH receptor antagonist with reasonably high affinity (34; K i ¼ 34 nM). The bioavailability of 34 was only 1.6% due to the high lipophilicity and poor metabolic stability.…”

Section: G Furamide Derivativesmentioning

confidence: 74%

“…Niida and co-workers 148 performed both an alanine and D-amino acid scan of KP-10 to identify important residues for GPR54 agonistic activity. It was shown that five amino acids (50)(51)(52)(53)(54) were important for receptor binding and activation. Incorporation of a basic group, for example, guanidine, and substitution of Phe with Trp resulted in the first significantly downsized peptide GPR54 agonist with similar potency as KP-10 (EC 50 ¼ 1.4 nM).…”

Section: G P R 4 R E C E P T O R L I G a N D Smentioning

confidence: 99%

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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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Section: G Furamide Derivativesmentioning

confidence: 74%

Section: G P R 4 R E C E P T O R L I G a N D Smentioning

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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“…In 2003, Zhu et al80 reported that a series of novel uracil derivatives [1-arylmethyl-3-(2-aminoethyl)–5-aryluracil] showed potent anti GnRHR activity. The group started a systematic evaluation of this class of compounds,81–86 and in 2008, Chen et al87 published the discovery of a potent and orally available nonpeptide antagonist of the GnRHR.…”

Section: Medical Treatmentmentioning

confidence: 99%

<p>Uterine fibroids: an update on current and emerging medical treatment options</p>

Farris

Bastianelli

Rosato

et al. 2019

TCRM

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Uterine fibroids are the most common gynecological disorder, classically requiring surgery when symptomatic. Although attempts at finding a nonsurgical cure date back to centuries, it is only around the middle of the last century that serious attempts at a medical treatment were carried out. Initially, both progestins and estrogen–progestin combinations have been utilized, although proof of their usefulness is lacking. A major step forward was achieved when peptide analogs of the GnRH were introduced, first those with superagonist properties and subsequently those acting as antagonists. Initially, the latter produced side effects preventing their routine utilization; eventually, this problem was overcome following the synthesis of cetrorelix. Because both types of analogs produce hypoestrogenism, their use is limited to a maximum of 6 months and, for this reason, today they are utilized as an adjuvant treatment before surgery with overall good results. Over the last decade, new, nonpeptidic, orally active GnRH-receptor blockers have also been synthesized. One of them, Elagolix, is in the early stages of testing in women with fibroids. Another fundamental development has been the utilization of the so-called selective progesterone receptor modulators, sometimes referred to as “antiprogestins”. The first such compound to be applied to the long-term treatment of fibroids was Mifepristone; today, this compound is mostly used outside of Western Countries, where the substance of choice is Ulipristal acetate. Large clinical trials have proven the effectiveness of Ulipristal in the long-term medical therapy of fibroids, although some caution must be exercised because of the rare occurrence of liver complications. All selective progesterone receptor modulators produce unique endometrial changes that are today considered benign, reversible, and without negative consequences. In conclusion, long-term medical treatment of fibroids seems possible today, especially in premenopausal women.

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“…2e ), which is consistent with previous structure–activity relationship studies, indicating that a large heteroaromatic ring substituent on arm3 is a promising candidate for GnRH1R 27 . The methyl group at position 6 of elagolix is suggested to be an additional critical moiety that contributes to high-affinity ligand binding 28 , probably by forcing arm3 ring into a different plane at approximately a 45° angle relative to the core plane, embedding arm3 into the hydrophobic pocket (Fig. 2e ).…”

Section: Resultsmentioning

confidence: 99%

Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

et al. 2020

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Gonadotrophin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). The GnRH-GnRH1R system is a promising therapeutic target for maintaining reproductive function; to date, a number of ligands targeting GnRH1R for disease treatment are available on the market. Here, we report the crystal structure of GnRH1R bound to the small-molecule drug elagolix at 2.8 Å resolution. The structure reveals an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix. The unusual ligand binding mode was further investigated by structural analyses, functional assays and molecular docking studies. On the other hand, because of the unique characteristic of lacking a cytoplasmic C-terminal helix, GnRH1R exhibits different microswitch structural features from other class A GPCRs. In summary, this study provides insight into the ligand binding mode of GnRH1R and offers an atomic framework for rational drug design.

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Identification of 1-Arylmethyl-3- (2-aminoethyl)-5-aryluracil as Novel Gonadotropin-Releasing Hormone Receptor Antagonists

Cited by 25 publications

References 7 publications

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

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

<p>Uterine fibroids: an update on current and emerging medical treatment options</p>

Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

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