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TW-202334178-A - KISS 1 PEPTIDE COMPOUND, APPLICATION THEREOF AND COMPOSITION CONTAINING THE SAME

TW202334178ATW 202334178 ATW202334178 ATW 202334178ATW-202334178-A

Abstract

The invention provides a Kiss1 peptide compound, an application thereof and a composition containing the same. The present invention provides a peptide compound of the formula I, a pharmaceutically acceptable salt thereof, a tautomer thereof, a solvate thereof, a crystalline form thereof or a prodrug thereof. The compound has better stability and better activity against Kiss1R.

Inventors

  • ANGELL YVONNE
  • WU YUN
  • WANG YAN
  • LIU WEI-MIN
  • FONG KIN CHIU
  • WEN JIE
  • HU YONGHAN

Assignees

  • SHANGPHARMA INNOVATION JIANGXI CO LTD

Dates

Publication Date
20230901
Application Date
20180705
Priority Date
20170705

Claims (6)

  1. A peptide compound 3, its pharmaceutically acceptable salt, its tautomer, its solvate or its crystal form, wherein the compound 3 is any of the following compounds: Ac-[D-Phe(2, 4-DiCl)]-(S-Pip)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH 2 , Ac-D-Phe(2,4-DiCl)-DiFluorPro-Asn-Thr -Phe-ψ(NHCS)G-Leu-Arg(Me)-Trp-NH 2 , Ac-(D-Tyr)-A6c-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH 2 .
  2. The use of a peptide compound 3 as described in claim 1, its pharmaceutically acceptable salts, its tautomers, its solvates or its crystal forms in the preparation of medicines for the treatment of and /or prevent kissing peptide receptor-related diseases.
  3. The application as described in claim 2, wherein the disease related to the kissing peptide receptor is one or more of a hormone-related disease, a cell proliferation disease, and a disease related to placenta function.
  4. The application as described in claim 3, wherein the hormone-related diseases are prostate cancer, breast cancer, endometriosis, uterine fibroids, central precocious puberty, estrogen receptor positivity, sexual dysfunction Illness, infertility, depression, or pregnancy; And/or, the cell proliferative disease is benign prostatic hyperplasia or cancer; And/or, the disease related to placental function is choriocarcinoma, invasive nevus, miscarriage, fetal hypoplasia, abnormal glucose metabolism or abnormal lipid metabolism.
  5. The application as described in claim 4, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, thyroid cancer, bladder cancer, liver cancer, melanoma, pancreatic cancer, Stomach, renal cell, esophageal, bladder or brain cancer.
  6. A pharmaceutical composition comprising compound 3 as described in claim 1, its pharmaceutically acceptable salt, its tautomer, its crystal form or its solvate, and pharmaceutical excipients.

Description

A Kiss1 peptide compound, its application and a composition containing the same The present invention relates to a Kiss1 peptide compound, its application and compositions containing it. Kiss-1 gene is a new type of gene that inhibits human melanoma metastasis discovered by Jeong-Hyung Lee and others (Lee JH, et. al. Journal of the National Cancer Institute, Vol. 88(23): 1731-1737 (1996) )). The Kiss-1 gene is located on human chromosome 1q32 and consists of four exons - two untranslated and two partially translated exons. It encodes a precursor polypeptide containing 145 amino acids. The precursor peptide is cleaved into Kisspeptin-54 (also known as metastin or metastastin) with a length of 54 amino acids, and can be further truncated to 14 [Kisspeptin-14/metastin (40-54)], 13 [ Kisspeptin-13/metastin(41-54)] or 10 [Kisspeptin-10/metastin(45-54)] amino acids; these truncations and precursors are collectively called Kisspeptin (Kisspeptin, Kp for short), and Highly conserved in mammals (Kotani M, et. Al. Journal of Biological Chemistry, Vol. 276(27): 34631-34636; Ohtaki T. et al., Nature Vol, 411(6837): 613-671 (2001 )). The four kissing peptides all contain the same 10 amino acid residues, with arginine and phenylalanine (RF-amide) at the C-terminus, but the polypeptide lengths at the N-terminus are different. The C-terminal part of kissing peptide is related to the efficient binding and activation of receptors. The activity of truncated peptides such as Kisspeptin-10 and Kisspeptin-14 is 3-10 times higher than Kisspeptin-54. Kiss-1 mRNA is mainly expressed in the human placenta and is also widely expressed in the entire central nervous system: the expression is highest in the shell, higher in the caudate nucleus, globus pallidus, hypothalamus, nucleus accumbens and cerebellum, and in the prefrontal lobe , amygdala, cingulate gyrus, hippocampal gyrus, parahippocampal gyrus, optic thalamus, substantia nigra, locus coeruleus, cerebellum oblongata, and very little expression in the spinal cord. It is currently known that the receptor for these kissing peptides (Kiss1R) is a member of the orphan G protein-coupled receptor retinoic acid family (called GPR54 in rats and AXOR12 in humans). Kiss1R contains 398 amino acid residues and is related to the galanin receptor family, but it does not bind to galanin. Rat GPR54 is highly conserved among mammals, with 81% homology with the human receptor and 85% homology with the mouse. Human Kiss1R mRNA is abundant in the placenta, subcerebral gland, spinal cord and pancreas, and in other tissues including different brains (optic thalamus, caudate nucleus, substantia nigra, hippocampus, amygdala, cerebellum), stomach, small intestine, The thymus, spleen, lungs, testes, kidneys, and fetal liver showed low levels. Kisspeptin and its receptors are distributed in the brain and peripheral tissues and organs, including the hypothalamus, aorta, ovary, prostate and placenta. The receptors are also expressed in the subbrain glands. Their functions include regulating reproductive function, affecting endocrine, and affecting the growth and metastasis of tumor cells. The signaling between kissing peptide and Kiss1R (GPR54) is to activate intracellular phospholipase C (PLC) after the polypeptide binds to its receptor, thereby hydrolyzing lipoinositol diphosphate (PIP2) to produce inositol triphosphate (IP3). ) and diacylglycerol (DAG), thereby promoting the increase of intracellular calcium ions, arachidonic acid release, protein kinase C (PKC) activation, extracellular signal-regulated kinase (ERK1 and ERK2) and p38 mitosis-activated protein kinase (MAPK) phosphorylation ation, thereby producing biological effects. An important role of kisspeptin and Kiss1R signaling is the initiation of secretion of gonadotropin-releasing hormone (GnRH) during puberty. The release of gonadotropin-releasing hormone is the action of the anterior lobe of the subbrain gland, which also includes the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Disruption of this signaling pathway results in insufficient GnRH release, resulting in hypogonadism in humans and rodents. Abnormal release or absence is the main cause of sexual reproductive abnormalities in men and women. Studies have shown that the GnRH analog kissing peptide works at the level of the hypothalamus to stimulate GnRH release (US7754220). Infusion of kissing peptide can stimulate GnRH release at all stages. Kiss1R activator is a method to prevent or treat hormone-related diseases such as prostate cancer, breast cancer, endometriosis, uterine fibroids, premenopausal breast cancer, central precocious puberty, and sexual dysfunction diseases. and used in in vitro fertilization to induce ovulation and as a new generation of contraceptive pills. Kissing peptide binds Kiss1R (GPR54) and has multiple functions, and inhibiting cell proliferation is an important one (Kotani M, et al., J. Biol. Chem. Vol 276: 34631-34636). Kiss1