Rational Design of Triazololipopeptides Analogs of Kisspeptin Inducing a Long-Lasting Increase of Gonadotropins

Abstract : New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-resistant amide mimic and a serum albumin-binding motif, respectively. These triazololipopeptides are highly potent full agonists of KISS1R and are >100 selective over the closely related NPFF1R. When injected in ewes with a quiescent reproductive system, the best compound of our series induced a much prolonged increase of luteinizing hormone release compared to KP10 and increased follicle-stimulating hormone plasma concentration. Hence, this KISS1R agonist is a new valuable pharmacological tool to explore the potential of KP system in reproduction control. Furthermore, it represents the first step to develop drugs treating reproductive system disorders due to a reduced activity of the hypothalamo–pituitary–gonadal axis such as delayed puberty, hypothalamic amenorrhea, and hypogonadotropic hypogonadism.
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https://hal.archives-ouvertes.fr/hal-01170460
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Submitted on : Wednesday, July 1, 2015 - 3:48:06 PM
Last modification on : Tuesday, June 4, 2019 - 4:30:08 PM

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Massimiliano Beltramo, Vincent Robert, Mathieu Galibert, Jean-Baptiste Madinier, Philippe Marceau, et al.. Rational Design of Triazololipopeptides Analogs of Kisspeptin Inducing a Long-Lasting Increase of Gonadotropins. Journal of Medicinal Chemistry, American Chemical Society, 2015, 58 (8), pp.3459-3470. ⟨10.1021/jm5019675⟩. ⟨hal-01170460⟩

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