Identification, synthesis, and biological evaluation of novel pyrazoles as low molecular weight luteinizing hormone receptor agonists

Jorand-Lebrun, Catherine; Brondyk, Bill; Lin, Jing; Magar, Sharad S.; Murray, Robert; Reddy, Adulla; Shroff, Hitesh N.; Wands, Greg; Weiser, Weishui Y.; Xu, Qihong; McKenna, Sean D.; Brugger, Nadia

doi:10.1016/j.bmcl.2006.12.062

Cited by 41 publications

(32 citation statements)

References 12 publications

(9 reference statements)

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“…3). 112 Pyrazole derivatives were identified from an in-house library screen. Subsequently, a new pyrazole library was synthesized to examine the SAR of these new ligands.…”

Section: B Pyrazole 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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“…3). 112 Pyrazole derivatives were identified from an in-house library screen. Subsequently, a new pyrazole library was synthesized to examine the SAR of these new ligands.…”

Section: B Pyrazole 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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“…Furthermore, Org-41841 was also found to induce ovulation in 40% of animals when administered at 50 mg/ kg. Recently, Jorand-Lebrun et al [76] have reported a series of pyrazole compounds that act as LHR and LHR/ FSHR partial agonists. The pyrazole LHR/FSHR agonist showed an approximate 7-fold selectivity for the LHR over the FSHR [77].…”

Section: Synthetic Small Molecule Fsh Agonists Mimic Biased Signalingmentioning

confidence: 99%

Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications

Arey

López

2011

Rev Endocr Metab Disord

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The gonadotropins, luteinizing hormone, human chorionic gonadotropin and follicle-stimulating hormone, are key regulators of reproduction. As a result of this function, they have been the focus of research for many years. Isolated or recombinant proteins have been successfully used therapeutically for the treatment of infertility; and, in the case of compounds that block gonadotropin activity, for their potential utility in contraception. Until recently, selective small molecules modulating gonadotropin receptor activity have proven difficult to identify. The gonadotropins are glycoproteins that are released into the plasma as differently glycosylated isoforms and bind to specific G protein-coupled receptors. The degree of glycosylation on the gonadotropins has been shown to be important for the biological activities of these hormones and is differentially regulated depending on the steroidal status. Recent data from the study of glycosylated variants of LH, hCG and FSH have revealed that these isoforms have distinct signaling properties that allow for gonadotropin pleiotropic signals to be transduced effectively at the level of the receptor. Thus, glycosylated variants of the gonadotropins behave as biased agonists. Recently, newly developed, small molecule, synthetic allosteric compounds have been identified that are capable of mimicking this biased signaling. This opens the door to development of orally available, drug-like therapies for reproductive disorders that offer similar pleiotropic richness as that offered by the complex, endogenous hormones.

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“…Compound 33 that increases testosterone levels in male rats is a LHR (Gonadotropin luteinizing hormone) agonist. 43 For pulmonary diseases like asthma, compound 34 (MRE 2029-F20) an A2B adenosine receptor antagonist 44 was studied. Derivative 35, a MR (Mineralocorticoid receptor) antagonist has been evaluated to treat hypertension.…”

Section: Directly Linkedmentioning

confidence: 99%

A review of recent progress (2002-2012) on the biological activities of pyrazoles

Pérez-Fernández¹,

Goya²,

Elguero³

2013

Arkivoc

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Dedicated to Professor Rosa M. Claramunt on the occasion of her 65 th anniversary AbstractIn this review, we report the structures of 243 pyrazoles with their corresponding biological activities. All of them are represented around the common structure of the pyrazole ring even in those cases where the heterocycle is only a minor part of the molecule. The classification we have used is based on chemical structure considerations and not in terms of the therapeutic area which is the more common approach. Some general conclusions have been drawn linking structures with activities.

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Identification, synthesis, and biological evaluation of novel pyrazoles as low molecular weight luteinizing hormone receptor agonists

Cited by 41 publications

References 12 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

Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications

A review of recent progress (2002-2012) on the biological activities of pyrazoles

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