Structure–activity relationships of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists

Wu, Dongpei; Zhu, Yunfei; Tucci, Fábio C.; Regan, B. C.; Rowbottom, Martin W.; Struthers, R. Scott; Xie, Qiu; Reijmers, Shelby; Sullivan, Susan K.; Sai, Yang; Chen, Chen

doi:10.1016/j.bmcl.2005.05.038

Cited by 12 publications

(7 citation statements)

References 17 publications

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“…65 Receptor affinity of 47 was fivefold improved by the introduction of a 2-fluoro substituent at the 5-phenyl group. 66 Substitution of the 2-fluoro by a bromo substituent at the N-1 benzyl group resulted in a 20-fold overall increase in potency (48; K i ¼ 2 nM). Compound 48 showed functional antagonism in an inositol phosphate accumulation assay (IC 50 ¼ 33 nM) and its metabolic stability was comparable to that of compound 39.…”

Section: J 135-triazine-246-trione Derivativesmentioning

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: J 135-triazine-246-trione Derivativesmentioning

confidence: 99%

“…127 Besides tetrahydroquinoline-based agonists, Figure 4. Chemical structure of the most potent gamma-lactam 124 (65) and tetrahydroquinoline 125 (66) derivative as an agonist at the human FSH receptor.…”

Section: Patented Agonistsmentioning

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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“…For example, fidarestat 113 and sorbinil 114 (anti-cancer/anti-diabetic) [113], brequinar 115 (antitumour/ immunosuppressive) [114], roflumilast 116 (anti-inflammatory/ chronic obstructive pulmonary diseases) [115], leflunomide 117 and VML-295 (LY293111) 118 (anti-cancer/psoriasis) [116], T0901317 119 and 2,4,6-trisubstituted pyridines 120 have been reported as potent farnesoid X receptor (FXR) modulators and they have emerged as target drugs for inflammation and cancers [117]. Fluorinated gonadotropin-releasing hormone (hGnRH) receptor antagonists 121 and 122 are in clinical development for the treatment of human reproductive diseases and gynecological cancer [118] and the steroid sulfatase inhibitors 123, 124 have recently been reported as more potent compounds than their non-fluorinated analogues 125, 126 as inhibitors of steroid dependent cancers [119].…”

Section: Miscellaneous Cancer Drugsmentioning

confidence: 99%

Fluorine in medicinal chemistry: A review of anti-cancer agents

Isanbor

O’Hagan

2006

Journal of Fluorine Chemistry

1,031

343

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“…The cells were preincubated with the appropriate concentrations of TAK-013 (or its analogs) for 20 min at 37°C before the addition of GnRH to stimulate inositol phosphate accumulation for 60 min. The inositol phosphates were then measured as described previously (Guo et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

Trapping of a Nonpeptide Ligand by the Extracellular Domains of the Gonadotropin-Releasing Hormone Receptor Results in Insurmountable Antagonism

et al. 2007

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Drugs that exhibit insurmountable antagonism are proposed to provide improved clinical efficacy through extended receptor blockade. Long-term suppression of the gonadotropin-releasing hormone receptor (GnRHR) is an important therapeutic approach for a number of sex hormone-dependent diseases. In this study, we describe the mechanism and structural components required for insurmountable activity of a GnRHR antagonist. TAK-013 behaves as an insurmountable antagonist at the human receptor (hGnRHR) but as a surmountable antagonist at the macaque receptor (mGnRHR). Mutation of the eight residues that differ between hGnRHR and mGnRHR identified Ser-203 and Leu-300 in extracellular loops (ECL) 2 and 3 of hGn-RHR as essential for the insurmountability of TAK-013. Substitution of the corresponding residues in mGnRHR with Ser and Leu (mGnRHR-P203S/V300L) converts TAK-013 to an insurmountable antagonist. In addition, mutation of Met-24 to Leu in the amino terminus of hGnRHR also ablates the insurmountable antagonism of TAK-013. The mechanism of insurmountability of TAK-013 was determined to be governed by its rate of dissociation from the receptor. Although the association rates of TAK-013 to hGnRHR, mGnRHR, and mGnRHR-P203S/ V300L do not differ, the dissociation rate half-life correlates closely with the degree of insurmountability observed (169, 9, and 55 min, respectively). Taken together, these data suggest a model of the GnRHR in which ECL2, ECL3, and the amino terminus engage with TAK-013 upon its binding to the transmembrane region of the receptor. These additional interactions form a "trap door" above TAK-013, restricting its dissociation and thus resulting in its insurmountability.

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Structure–activity relationships of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists

Cited by 12 publications

References 17 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

Fluorine in medicinal chemistry: A review of anti-cancer agents

Trapping of a Nonpeptide Ligand by the Extracellular Domains of the Gonadotropin-Releasing Hormone Receptor Results in Insurmountable Antagonism

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