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Beltramo, M., Robert, V., Galibert, M., Madinier, J.-B., Marceau, P., Dardente, H., Decourt, C., De Roux, N., Lomet, D., Delmas, A. F., Caraty, A. and Aucagne, V.

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

Journal of Medicinal Chemistry (2015) 58 (8) 3459-3470 - doi : 10.1021/jm5019675

by Frapart - published on , updated on


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.