JP6253146B2 - Novel peptide derivative and pharmaceutical containing the same - Google Patents
Novel peptide derivative and pharmaceutical containing the same Download PDFInfo
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- JP6253146B2 JP6253146B2 JP2014019236A JP2014019236A JP6253146B2 JP 6253146 B2 JP6253146 B2 JP 6253146B2 JP 2014019236 A JP2014019236 A JP 2014019236A JP 2014019236 A JP2014019236 A JP 2014019236A JP 6253146 B2 JP6253146 B2 JP 6253146B2
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
本発明は、(a)Tyr−Asn−Trp−Asn−Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号1)、(b)Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号2)、(ただし、上記Rは炭素数1−20の置換又は非置換の直鎖状若しくは分枝状のアルキル基である)から選択されるペプチド誘導体、若しくはその塩、又はそれらの溶媒和物に関する。 The present invention, -Phe-Gly- (a) Tyr -Asn-Trp-Asn-Ser (COR) -Phe-Gly-Leu-Arg-Tyr-NH 2 ( Compound No. 1), (b) Ser ( COR) Peptide derivative selected from Leu-Arg-Tyr-NH 2 (Compound No. 2) (wherein R is a substituted or unsubstituted linear or branched alkyl group having 1 to 20 carbon atoms) Or a salt thereof, or a solvate thereof.
ヒト・メラノーマ細胞より同定されたがん転移抑制遺伝子のKISS1遺伝子[非特許文献1]を始原とするKISS1遺伝子産物は、145個のアミノ酸からなり、フーリン(furin)やホルモン前駆体変換酵素などによって分割され、54個のアミノ酸からなるキスペプチン(キスペプチン−54)を形成する。キスペプチンと同時期にヒト胎盤から同定された、KISS1遺伝子を起源とするがん転移抑制物質のメタスチン[非特許文献2][特許文献1]は、キスペプチンと同一物質として知られる。キスペプチンとメタスチンは共に、低ゴナドトロピン性性腺低形成症患者において遺伝子変異が見つかったGタンパク質共役受容体54(GPR54)に対するリガンドであり、カルボキシ末端(C末端)側で切断されたKiSS−1遺伝子産物のC末端がアミド化された54アミノ酸ペプチドである[非特許文献3]。 The KISS1 gene product originated from the KISS1 gene [Non-patent Document 1], a cancer metastasis suppressor gene identified from human melanoma cells, consists of 145 amino acids, and is produced by furin, hormone precursor converting enzyme, etc. Divided to form kisspeptin (kisspeptin-54) consisting of 54 amino acids. Metastin [Non-patent Document 2] [Patent Document 1], which is a cancer metastasis inhibitor originating from the KISS1 gene, identified from the human placenta at the same time as kisspeptin is known as the same substance as kisspeptin. Both kisspeptin and metastin are ligands for G protein-coupled receptor 54 (GPR54) whose gene mutation was found in hypogonadotropic hypogonadism patients, and the KiSS-1 gene product cleaved on the carboxy terminus (C terminus) side Is a 54 amino acid peptide in which the C-terminal is amidated [Non-patent Document 3].
キスペプチンは、脊椎動物脳内のおもに視床下部にある神経細胞、及び下垂体がつくるペプチドホルモンの一種であり、性腺刺激ホルモン放出ホルモン(GnRH)を分泌する神経細胞や、黄体形成ホルモン(LH)を分泌する下垂体前葉細胞を刺激する作用が報告されている[非特許文献4]。 Kispeptin is a type of peptide hormone produced by the hypothalamus and the hypothalamus in the vertebrate brain. It contains neurons that secrete gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). An effect of stimulating secretory anterior pituitary cells has been reported [Non-Patent Document 4].
キスペプチン−54は、更に短いアミノ酸配列をとるキスペプチン−10などに分割され、C末端側の10個のアミノ酸からなるペプチド(キスペプチン−10)が、キスペプチンの生理効果をもたらすとされるコア部分であると考えられている。ヒトのキスペプチン−54及びキスペプチン−10はいずれもC末端に共通の−Arg−Phe−NH2(RF−NH2)構造を有するが、ラット、マウスなどのげっ歯類、ウシ、ヤギ、ヒツジといった反芻動物、並びにブタを含めた家畜のキスペプチン−54及びキスペプチン−10は、いずれもC末端に−Arg−Tyr−NH2(RY−NH2)構造を有する[非特許文献3,5]。また、ヒトと上記動物間のアミノ酸置換(Tyr→Phe)は、キスペプチンのゴナドトロピン分泌促進作用に影響を与えないことも明らかとなっており、従って、キスペプチン−10やその類縁ペプチドが、種を超えた生殖制御を可能とするホルモン製剤としても有用と考えられる[非特許文献5]。 Kispeptin-54 is divided into kisspeptin-10 or the like having a shorter amino acid sequence, and a peptide consisting of 10 amino acids on the C-terminal side (kisspeptin-10) is a core part that is supposed to bring about the physiological effect of kisspeptin. It is believed that. Kisspeptin -54 and kisspeptin human has a common -Arg-Phe-NH 2 (RF -NH 2) structure to the C-terminus both, rats, rodents such as mice, cows, goats, such sheep ruminants, and kisspeptin -54 and kisspeptin livestock, including pigs, all have -Arg-Tyr-NH 2 (RY -NH 2) structure to the C-terminus [non-Patent Document 3, 5]. It has also been clarified that amino acid substitution (Tyr → Phe) between humans and the above animals does not affect the gonadotropin secretion promoting action of kisspeptin. Therefore, kisspeptin-10 and its related peptides exceed species. It is also considered useful as a hormone preparation that enables reproductive control [Non-patent Document 5].
生殖を司る内因性神経ペプチドのキスペプチンは、家畜の繁殖をコントロールする製剤として利用しうる。乳用牛及び肉用牛の生産現場では、人工授精対象牛の微弱発情や、それにともなう交配適期の見逃しなどによる受胎成績の低下、またブタの場合は、雄ブタを許容しない雌ブタの鈍性発情や発情の見落としにより、交配適期を逸し、結果的に受胎不成立となることが、常態的な問題となっている。これまで報告されている種々の方法(プロスタグランジンF2αの反復投与、ウマ絨毛性性腺刺激ホルモン(eCG又はPMSG)とヒト絨毛性性腺刺激ホルモン(hCG)の併用投与など)をもってしても確実な交配技術は確立されておらず、ウシやブタの発情同期化の難しさが生産性を高めるための障壁となっている[非特許文献5]。 The endogenous neuropeptide kisspeptin that controls reproduction can be used as a preparation for controlling reproduction of livestock. At production sites for dairy and beef cattle, the fertility declines due to weak estrus of cattle subject to artificial insemination and the appropriate mating period, and in the case of pigs, the dullness of sows that do not allow male pigs It is a normal problem that estrus or overestablishment of estrus leads to a lack of mating, resulting in infertility. Even with various methods reported so far (repeated administration of prostaglandin F2α, combined administration of equine chorionic gonadotropin (eCG or PMSG) and human chorionic gonadotropin (hCG), etc.) The mating technology has not been established, and the difficulty in synchronizing estrus in cattle and pigs has become a barrier for increasing productivity [Non-Patent Document 5].
近年のウシやブタの受胎成績低下の要因については、育種学的な改良によって高い泌乳量や急速な増体などの形質を優先してきた結果として、肝心の繁殖機能が低下した可能性が指摘されている。また、これまでウシやブタの発情同期化・過排卵処置に多用されてきたeCGやhCGなどの異種のホルモン製剤では、その反復投与によって抗体が作られ、結果的にホルモン製剤の効力が落ちてしまうという問題がある。上記に挙げた問題を解決するためには、種を超えた生殖制御を可能とするホルモン製剤の開発が必要である。 Regarding the cause of decline in fertility in recent years in cattle and pigs, it has been pointed out that as a result of the improvement of breeding, priority has been given to traits such as high milk yield and rapid weight gain. ing. In addition, in different types of hormonal preparations such as eCG and hCG that have been frequently used for estrus synchronization and superovulation treatment in cattle and pigs, antibodies are produced by repeated administration, resulting in a decrease in the efficacy of the hormonal preparation. There is a problem of end. In order to solve the above-mentioned problems, it is necessary to develop a hormone preparation that enables reproductive control across species.
キスペプチンは、癌転移抑制作用を有することでも知られており、肺癌、胃癌、肝癌、膵癌、大腸癌、直腸癌、結腸癌、前立腺癌、卵巣癌、子宮頚癌、乳癌、腎癌、膀胱癌、脳腫瘍などの予防・治療、膵臓機能調節作用による膵臓疾患(急性または慢性膵炎、膵癌など)の予防・治療、胎盤機能調節作用による絨毛癌、胞状奇胎、侵入奇胎、流産、胎児の発育不全、糖代謝異常、脂質代謝異常または分娩異常の予防・治療に有効であるとの報告がある[特許文献2]。 Kispeptin is also known to have a cancer metastasis-inhibiting action, lung cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, kidney cancer, bladder cancer , Prevention / treatment of brain tumors, prevention / treatment of pancreatic diseases (acute or chronic pancreatitis, pancreatic cancer, etc.) by regulating pancreatic function, choriocarcinoma, hydatidiform mole, invasion, miscarriage, fetal development by regulating placental function There is a report that it is effective for the prevention and treatment of insufficiency, abnormal sugar metabolism, abnormal lipid metabolism or abnormal labor [Patent Document 2].
また、ホルモン感受性癌である前立腺癌に対する内分泌療法において、GnRH受容体を持続的に刺激することで脱感作させ、その結果GnRHの作用抑制により、精巣からの男性ホルモン分泌を防ぐ目的で、GPR54アゴニスト(作動薬)が従来的に使用されている。この様な背景から、新規GPR54アゴニスト創薬の分野では、TAK−448([Ac][D]Tyr−Hyp−Asn−Thr−Phe−[aza]Gly−Leu−Arg[Me]−Trp−NH2)を代表とする[非特許文献6]キスペプチン誘導体の開発及び臨床試験が進められている。 Further, in endocrine therapy for prostate cancer, which is a hormone-sensitive cancer, GPRRH receptor is desensitized by continuously stimulating GnRH receptor, and as a result, GrRH suppresses the action of GnRH to prevent male hormone secretion from the testis. Agonists are conventionally used. Against this background, in the field of novel GPR54 agonist drug discovery, TAK-448 ([Ac] [D] Tyr-Hyp-Asn-Thr-Phe- [aza] Gly-Leu-Arg [Me] -Trp-NH2 [Non-patent document 6] kisspeptin derivatives and clinical trials are underway.
他にも、GPR54のアゴニスト及びアンタゴニスト(拮抗薬)として、ヒトのキスペプチン−10及びキスペプチン−6のN末端をアセチル化した例は、過去に報告されているが[非特許文献7]、n−オクタン酸でアシル化修飾されたGPR54アゴニストであるキスペプチン誘導体の例はない。 In addition, as an agonist and antagonist (antagonist) of GPR54, an example of acetylating the N-terminus of human kisspeptin-10 and kisspeptin-6 has been reported in the past [Non-patent Document 7], n- There are no examples of kisspeptin derivatives that are GPR54 agonists acylated with octanoic acid.
セリン残基がn−オクタン酸でアシル化修飾された構造を有する他のペプチドホルモンとしては、成長ホルモン分泌促進ペプチドのグレリン(ghrelin)が、胃から単離されているものの、n−オクタノイル化された他の天然ペプチドは、哺乳類でこれまで見出されていない[非特許文献8]。同定された上記グレリンは、求心性の迷走神経に作用し、その情報が視床下部に到達、摂食を促進させることが知られている。一方、視床下部の神経細胞が分泌するキスペプチンを、合成的にn−オクタノイル化させたペプチドが、下垂体前葉細胞を刺激しLHを分泌させるという知見はない。 As another peptide hormone having a structure in which the serine residue is acylated and modified with n-octanoic acid, the growth hormone secretagogue peptide ghrelin has been isolated from the stomach but is n-octanoylated. Other natural peptides have not been found in mammals [8]. It is known that the identified ghrelin acts on the afferent vagus nerve, and the information reaches the hypothalamus to promote feeding. On the other hand, there is no finding that a peptide in which kisspeptin secreted by neurons in the hypothalamus is synthetically n-octanoylated stimulates anterior pituitary cells and secretes LH.
キスペプチンをはじめとする生理活性ペプチドは、一般的に生体内において変性しやすく、また酵素によって容易に分解され、安定性が低い。よってペプチド製剤を使用する場合、充分な薬理効果を得るためには、高投与量かつ長期間投与が必要となるが、主な投与法である注射を頻繁に施すと侵襲性が問題となる。従って、より生理活性の高いキスペプチンが臨床的有用性を秘めていることから、種や投与回数などに制約のない、優れたホルモン製剤として、より作用の強いキスペプチン剤の開発が望まれている。 Physiologically active peptides such as kisspeptin are generally easily denatured in vivo, are easily degraded by enzymes, and have low stability. Therefore, when a peptide preparation is used, in order to obtain a sufficient pharmacological effect, a high dose and long-term administration are required, but invasiveness becomes a problem when injection, which is the main administration method, is frequently performed. Therefore, since kisspeptin having higher physiological activity has clinical usefulness, development of a kisspeptin agent having a higher action as an excellent hormone preparation with no restrictions on species and the number of administrations is desired.
本発明の課題は、家畜の繁殖において、発情同期化・過排卵処置に多用されてきた異種のホルモン製剤では、反復投与によって抗体が作られ、結果的に製剤の効力が低下してしまうという問題があったことに鑑み、この問題に対する優れたホルモン製剤として、またはホルモン感受性癌の予防・治療及び転移抑制剤として、より作用の強いキスペプチン剤を提供することにある。 The problem of the present invention is that, in the breeding of livestock, in the case of heterologous hormone preparations that have been frequently used for estrus synchronization and superovulation treatment, antibodies are produced by repeated administration, resulting in a decrease in the efficacy of the preparations. In view of the above, it is an object of the present invention to provide a kisspeptin agent having a stronger effect as an excellent hormonal preparation for this problem, or as a prophylactic / therapeutic treatment and metastasis inhibitor for hormone-sensitive cancer.
本発明者らは、上記課題を解決すべく鋭意検討する中で、キスペプチンの活性中心である構成アミノ酸を特定の修飾基で修飾することにより、ウシ下垂体前葉細胞からのLH分泌量の指標において、予想外にも天然型キスペプチンより優れた生理活性を示すペプチド誘導体を見いだし、本発明を完成するに至った。 The inventors of the present invention have intensively studied to solve the above-mentioned problems. By modifying a constituent amino acid that is an active center of kisspeptin with a specific modifying group, the present invention can be used as an indicator of LH secretion from bovine pituitary cells. Unexpectedly, a peptide derivative having a physiological activity superior to that of natural kisspeptin was found, and the present invention was completed.
すなわち、本発明は以下の通りのものである。
(1)(a)Tyr−Asn−Trp−Asn−Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号1);(b)Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号2);(ただし、上記Rは炭素数1−20の置換又は非置換の直鎖状若しくは分枝状のアルキル基である)から選択されるペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
(2)Rが、n−ペンチル基、n−ヘキシル基、n−ヘプチル基、n−オクチル基及びn−ノニル基から選ばれるアルキル基である上記(1)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
(3)上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする医薬。
(4)上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする性腺刺激ホルモン放出ホルモン及び黄体形成ホルモン分泌促進剤。
(5)上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする家畜用繁殖制御剤。
(6)上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする、若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療剤。
That is, the present invention is as follows.
(1) (a) Tyr- Asn-Trp-Asn-Ser (COR) -Phe-Gly-Leu-Arg-Tyr-NH 2 ( Compound No. 1); (b) Ser ( COR) -Phe-Gly-Leu A peptide derivative selected from -Arg-Tyr-NH 2 (Compound No. 2); wherein R is a substituted or unsubstituted linear or branched alkyl group having 1 to 20 carbon atoms, Or a salt thereof, or a solvate thereof.
(2) The peptide derivative according to the above (1), or a salt thereof, wherein R is an alkyl group selected from an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group and an n-nonyl group. Or a solvate thereof.
(3) A medicament comprising the peptide derivative according to (1) or (2) above, or a salt thereof, or a solvate thereof as an active ingredient.
(4) A gonadotropin-releasing hormone and luteinizing hormone secretion promoter comprising the peptide derivative according to (1) or (2) above, or a salt thereof, or a solvate thereof as an active ingredient.
(5) A reproduction control agent for livestock comprising the peptide derivative according to (1) or (2) above, or a salt thereof, or a solvate thereof as an active ingredient.
(6) Juvenile climacteric disorder, menstrual abnormality, ovulation disorder, infertility, reproductive dysfunction, comprising the peptide derivative according to (1) or (2) above, or a salt thereof, or a solvate thereof as an active ingredient, A preventive and / or therapeutic agent for endometriosis, cancer metastasis, hormone-sensitive cancer.
また、本発明の他の態様として以下のものを例示することができる。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の、医薬を調製のための使用。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の、性腺刺激ホルモン放出ホルモン及び黄体形成ホルモン分泌促進剤を調製のための使用。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の、家畜用繁殖制御剤を調製のための使用。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の、若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療剤を調製のための使用。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の有効量を対象に投与する疾病の治療方法。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の有効量を対象に投与する性腺刺激ホルモン放出ホルモン及び黄体形成ホルモンの分泌促進方法。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の有効量を家畜に投与する繁殖制御方法。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の有効量を対象に投与する若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療方法。
疾病の治療に用いるための上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
性腺刺激ホルモン放出ホルモン及び黄体形成ホルモンの分泌促進に用いるための上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
家畜の繁殖制御に用いるための上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療に用いるための上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
Moreover, the following can be illustrated as another aspect of this invention.
Use of the peptide derivative according to the above (1) or (2), or a salt thereof, or a solvate thereof for preparing a medicament.
Use of the peptide derivative according to the above (1) or (2), or a salt thereof, or a solvate thereof for preparing a gonadotropin releasing hormone and a luteinizing hormone secretagogue.
Use of the peptide derivative according to the above (1) or (2), or a salt thereof, or a solvate thereof for the preparation of a livestock reproduction control agent.
Juvenile menopause, menstrual abnormalities, ovulation disorders, infertility, reproductive dysfunction, endometriosis, cancer metastasis of the peptide derivative according to (1) or (2) above, or a salt thereof, or a solvate thereof Use for the preparation of a prophylactic and / or therapeutic agent for hormone-sensitive cancer.
A method for treating a disease, wherein an effective amount of the peptide derivative according to the above (1) or (2), or a salt thereof, or a solvate thereof is administered to a subject.
A method for promoting secretion of gonadotropin-releasing hormone and luteinizing hormone, wherein an effective amount of the peptide derivative according to (1) or (2) above, or a salt thereof, or a solvate thereof is administered to a subject.
A reproduction control method comprising administering an effective amount of the peptide derivative according to the above (1) or (2), or a salt thereof, or a solvate thereof to livestock.
Juvenile climacteric disorder, menstrual abnormalities, ovulation disorders, infertility, reproductive dysfunction, uterus, administered to a subject an effective amount of the peptide derivative according to (1) or (2) above, or a salt thereof, or a solvate thereof A method for preventing and / or treating endometriosis, cancer metastasis, hormone-sensitive cancer.
The peptide derivative according to the above (1) or (2), or a salt thereof, or a solvate thereof for use in treating a disease.
The peptide derivative according to the above (1) or (2), or a salt thereof, or a solvate thereof for use in promoting secretion of gonadotropin releasing hormone and luteinizing hormone.
The peptide derivative according to the above (1) or (2), or a salt thereof, or a solvate thereof for use in controlling the reproduction of livestock.
Peptide according to (1) or (2) above for use in the prevention and / or treatment of juvenile menopause, menstrual abnormalities, ovulation disorders, infertility, reproductive dysfunction, endometriosis, cancer metastasis, hormone sensitive cancer Derivatives, salts thereof, or solvates thereof.
本発明による、より生理活性の強いキスペプチン剤を用いることで、家畜の繁殖における交配技術の向上、またはホルモン感受性癌の予防・治療及び転移抑制が期待される。具体的には、発情同期化・過排卵処置に多用されてきた、異種ホルモン製剤の反復投与による、好ましくない免疫反応の誘発や、結果としておこるホルモン製剤の効力低下を回避することが可能となり、より侵襲性が低く、かつ、畜種や投与回数などに制約のない、優れたホルモン処置プログラムやホルモン製剤の開発が可能となる。 By using the more physiologically active kisspeptin agent according to the present invention, it is expected to improve the mating technique in the breeding of livestock or to prevent / treat and suppress metastasis of hormone-sensitive cancer. Specifically, it has become possible to avoid undesired immune responses induced by repeated administration of heterologous hormone preparations that have been frequently used for estrus synchronization and superovulation treatment, and the resulting decrease in the efficacy of hormone preparations, It is possible to develop an excellent hormonal treatment program and a hormone preparation that are less invasive and have no restrictions on the breed of animals or the number of administrations.
本発明のペプチド誘導体としては、(a)化合物番号1に示す、Tyr−Asn−Trp−Asn−Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2、(b)化合物番号2に示す、Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2、から選択され、かかるペプチド誘導体、若しくはその塩、又はそれらの溶媒和物は、視床下部の神経細胞を刺激しGnRHの産生誘導活性を有し、且つ下垂体前葉細胞を刺激しLHの分泌を誘導するペプチドホルモンとして機能する。 Examples of the peptide derivatives of the present invention include (a) Tyr-Asn-Trp-Asn-Ser (COR) -Phe-Gly-Leu-Arg-Tyr-NH 2 , (b) Compound No. 2 Ser (COR) -Phe-Gly-Leu-Arg-Tyr-NH 2 , such a peptide derivative, or a salt thereof, or a solvate thereof, stimulates neurons in the hypothalamus and exhibits GnRH It has a production-inducing activity and functions as a peptide hormone that stimulates anterior pituitary cells and induces secretion of LH.
上記ペプチド誘導体において、Rは炭素数1−20の置換又は非置換の直鎖状若しくは分枝状のアルキル基である。具体的にはRは、メチル基、エチル基、プロピル基、イソプロピル基、n−ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基、n−ペンチル基、1-メチルブチル基、2-メチルブチル基、3-メチルブチル基、1,1-ジメチルプロピル基、1,2-ジメチルプロピル基、2,2-ジメチルプロピル基、3−ペンチル基、n−ヘキシル基、1-メチルヘプチル基、2-メチルヘプチル基、3-メチルヘプチル基、4-メチルヘプチル基、1,1-ジメチルブチル基、1,2-ジメチルブチル基、1,3-ジメチルブチル基、2,2-ジメチルブチル基、2,3-ジメチルブチル基、3,3-ジメチルブチル基、3,3-ジメチルブタン−2−イル基、2,3-ジメチルブタン−2−イル基、3−ヘキシル基、2-エチルペンチル基、2-メチルペンタン−3−イル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基、トリデシル基、テトラデシル基、ペンタデシル基、ヘキサデシル基、ヘプタデシル基、オクタデシル基、ノナデシル基、イコシル基等が挙げられる。本発明のペプチド誘導体において、Rとして、好ましくは置換又は非置換のn−ペンチル基、n−ヘキシル基、n−ヘプチル基、n−オクチル基、及びn−ノニル基であり、より好ましくは非置換のn−ペンチル基、n−ヘキシル基、n−ヘプチル基、n−オクチル基、及びn−ノニル基であり、さらに好ましくは非置換のn−ヘキシル基、n−ヘプチル基、及びn−オクチル基であり、最も好ましくは非置換のn−ヘプチル基である。
Rの置換基としては、フッ素、塩素、臭素、ヨウ素等のハロゲン、ヒドロキシル基、チオール基、アミノ基、ニトロ基、シアノ基、R1Oで表すことのできるアルコキシ基、R2COで表すことのできるアシル基、R3CO2で表すことのできるアシルオキシ基、R4Sで表すことのできるアルキルチオ基、R5SOで表すことのできるアルキルスルフィニル基、R6SO2で表すことのできるアルキルスルホニル基、R7SO3で表すことのできるアルキルスルホニルオキシ基、R8NHで表すことのできるアルキルアミノ基、R8R9Nで表すことのできるジアルキルアミノ基が挙げられる。ここでR1〜R9としては、上記Rと同様のアルキル基を用いることができる。R1〜R9として、好ましくは炭素数1〜3のアルキル基、さらに好ましくはメチル基である。
In the above peptide derivative, R is a substituted or unsubstituted linear or branched alkyl group having 1 to 20 carbon atoms. Specifically, R is methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl. Group, 3-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 3-pentyl group, n-hexyl group, 1-methylheptyl group, 2-methyl Heptyl group, 3-methylheptyl group, 4-methylheptyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3 -Dimethylbutyl group, 3,3-dimethylbutyl group, 3,3-dimethylbutan-2-yl group, 2,3-dimethylbutan-2-yl group, 3-hexyl group, 2-ethylpentyl group, 2- Methylpenta -3-yl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, etc. It is done. In the peptide derivative of the present invention, R is preferably a substituted or unsubstituted n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, and n-nonyl group, more preferably unsubstituted. N-pentyl group, n-hexyl group, n-heptyl group, n-octyl group and n-nonyl group, more preferably unsubstituted n-hexyl group, n-heptyl group and n-octyl group. And most preferably an unsubstituted n-heptyl group.
As the substituent for R, halogen such as fluorine, chlorine, bromine and iodine, hydroxyl group, thiol group, amino group, nitro group, cyano group, alkoxy group which can be represented by R 1 O, and R 2 CO An acyl group that can be represented by R 3 CO 2 , an alkylthio group that can be represented by R 4 S, an alkylsulfinyl group that can be represented by R 5 SO, and an alkyl that can be represented by R 6 SO 2 Examples thereof include a sulfonyl group, an alkylsulfonyloxy group that can be represented by R 7 SO 3 , an alkylamino group that can be represented by R 8 NH, and a dialkylamino group that can be represented by R 8 R 9 N. Here, as R 1 to R 9 , the same alkyl group as R can be used. R 1 to R 9 are preferably an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group.
さらに本発明のペプチド誘導体には、化合物番号1及び/又は化合物番号2で表される化合物を構成するアミノ酸配列において、1〜3個、好ましくは1又は2個、特に好ましくは1個のアミノ酸が、欠失、置換、挿入又は付加したアミノ酸配列を有し、かつ、GnRH及びLHの分泌促進活性を有する化合物、より好ましくは、視床下部の神経細胞を刺激しGnRHの産生誘導活性を有し、且つ下垂体前葉細胞を刺激しLHの分泌を誘導するペプチドホルモンとして機能する化合物も便宜上含まれる。キスペプチン−10(化合物番号3)のC末端アミノ酸であるTyrや、N末端から2つ目に存在するArg及びLeuは、それぞれ置換及び/又は欠失しても活性が保たれることが知られており、本発明のペプチド誘導体においてもアミノ酸が部分的に置換及び/又は欠失したとても、構造が維持され、上記活性機能を依然として有すると考えられる。このようにアミノ酸が部分的に置換及び/又は欠失したペプチド誘導体としては、例えば化合物番号1に示すTyr−Asn−Trp−Asn−Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2のC末端のアミド化されたチロシン(−Tyr−NH2)が、アミド化されたフェニルアラニン(−Phe−NH2)に置換された化合物や、化合物番号2に示すSer(COR)−Phe−Gly−Leu−Arg−Tyr−NH2のアミド化されたチロシン(−Tyr−NH2)が、アミド化されたフェニルアラニン(−Phe−NH2)に置換された化合物などを例示することができる。 Furthermore, the peptide derivative of the present invention contains 1 to 3, preferably 1 or 2, particularly preferably 1 amino acid in the amino acid sequence constituting the compound represented by Compound No. 1 and / or Compound No. 2. A compound having an amino acid sequence deleted, substituted, inserted or added and having a secretory promoting activity of GnRH and LH, more preferably stimulating neurons in the hypothalamus and having a GnRH production-inducing activity, Also included for convenience are compounds that function as peptide hormones that stimulate anterior pituitary cells and induce LH secretion. It is known that Tyr, which is the C-terminal amino acid of kisspeptin-10 (Compound No. 3), and Arg and Leu present second from the N-terminus, retain their activity even if they are substituted and / or deleted. In the peptide derivatives of the present invention, it is considered that the amino acid is partially substituted and / or deleted, the structure is maintained, and the active function is still maintained. Examples of peptide derivatives in which amino acids are partially substituted and / or deleted include Tyr-Asn-Trp-Asn-Ser (COR) -Phe-Gly-Leu-Arg-Tyr-NH shown in Compound No. 1, for example. 2 C-terminal amidated tyrosine (-Tyr-NH 2) is a compound substituted with an amidated phenylalanine (-Phe-NH 2) or, Ser shown in compound No. 2 (COR) -Phe- Gly-Leu-Arg-Tyr- NH 2 of the amidated tyrosine (-Tyr-NH 2) is, and the like can be exemplified amidated compounds substituted phenylalanine (-Phe-NH 2).
本発明のペプチド誘導体において、ラット、マウスなどのげっ歯類、ウシ、ヤギ、ヒツジといった反芻動物、並びにブタを含めた家畜におけるキスペプチンの、C末端−Arg−Tyr−NH2(RY−NH2)構造と、ヒトのC末端−Arg−Phe−NH2(RF−NH2)構造との間のアミノ酸置換(Tyr→Phe)は、キスペプチンのゴナドトロピン分泌促進作用に影響を与えないことから、本発明のペプチド誘導体の投与対象として、マウス、ラット、ハムスター、モルモット、ウサギ、ヤギ、ヒツジ、ロバ、ブタ、ウシ、ウマ、イヌ、ネコ、ニワトリ、サル、ヒト等を例示することができる。 In the peptide derivative of the present invention, C-terminal-Arg-Tyr-NH 2 (RY-NH 2 ) of kisspeptin in rodents such as rats and mice, ruminants such as cattle, goats and sheep, and livestock including pigs. The amino acid substitution (Tyr → Phe) between the structure and the human C-terminal-Arg-Phe-NH 2 (RF-NH 2 ) structure does not affect the gonadotropin secretion promoting action of kisspeptin. Examples of the subject of administration of the peptide derivative are mouse, rat, hamster, guinea pig, rabbit, goat, sheep, donkey, pig, cow, horse, dog, cat, chicken, monkey, human and the like.
本発明のペプチド誘導体を作製する方法としては特に制限されず、本発明のペプチド誘導体の母体となるペプチド(アミノ酸オリゴマー)の合成法としては、アミノ酸をアミド化により順次伸長する方法や、数個のアミノ酸からなるアミドセグメントを結合する方法がある。アミノ酸をアミド化により順次伸長する方法としては、例えば高分子にアミノ酸を結合させ、別のアミノ酸を結合させていく固相合成方法が挙げられる。また、有機化学的合成法の他にも、アミノ酸配列をコードしたDNA断片を組み込んだベクターを、大腸菌、酵母、昆虫細胞、哺乳動物細胞といった発現系を用いて合成させる、公知の遺伝子工学的ペプチド合成法に従って製造することもできる。
また、反応後は通常の精製法、たとえば、溶媒抽出・蒸留・カラムクロマトグラフィー・液体クロマトグラフィー・再結晶などの精製法を組み合わせて本発明のペプチドを精製単離することができる。上記方法で得られるペプチドが遊離体である場合は公知の方法によって適当な塩に変換することができ、逆に塩で得られた場合は、公知の方法によって遊離体に変換することができる。
The method for producing the peptide derivative of the present invention is not particularly limited, and a method for synthesizing a peptide (amino acid oligomer) serving as a base of the peptide derivative of the present invention includes a method of sequentially extending amino acids by amidation, There is a method of binding an amide segment composed of amino acids. Examples of the method of sequentially extending amino acids by amidation include a solid phase synthesis method in which an amino acid is bound to a polymer and another amino acid is bound. In addition to organic chemical synthesis methods, known genetically engineered peptides that synthesize vectors incorporating DNA fragments encoding amino acid sequences using expression systems such as E. coli, yeast, insect cells, and mammalian cells. It can also be produced according to synthetic methods.
Further, after the reaction, the peptide of the present invention can be purified and isolated by combining ordinary purification methods, for example, purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography, and recrystallization. When the peptide obtained by the above method is a free form, it can be converted into an appropriate salt by a known method. Conversely, when it is obtained as a salt, it can be converted into a free form by a known method.
以下に、固相合成法を用いた本発明のペプチドの合成法の一例を示す。 An example of a method for synthesizing the peptide of the present invention using the solid phase synthesis method is shown below.
固相合成に用いる担体としては、固相合成法に用いることのできる担体であればいかなる担体を用いても良いが、通常は樹脂(レジン)にリンカーを介してペプチド鎖のC末端のカルボキシル基と結合することのできる担体を用いる。このような固相担体の代表的な例としてはWangレジン、AMレジン、TGRレジン等を挙げることができるが、これらに限られるものではない。これらの担体が購入時等に膨潤していない状態であれば、合成に先立って膨潤させる必要がある。担体を膨潤させるための溶媒としては、担体がペプチド合成に用いることができる程度に膨潤する溶媒であれば、いかなる溶媒も用いることができるが、好ましくはN,N−ジメチルホルムアミド(DMF)又はジクロロメタン(DCM)である。膨潤した担体はろ過等により溶媒中から取り出すことができる。 As the carrier used for the solid phase synthesis, any carrier can be used as long as it can be used for the solid phase synthesis method. Usually, the carboxyl group at the C-terminal of the peptide chain is bonded to the resin (resin) via a linker. A carrier capable of binding to is used. Typical examples of such a solid support include, but are not limited to, Wang resin, AM resin, TGR resin, and the like. If these carriers are not swollen at the time of purchase or the like, they need to be swollen prior to synthesis. As the solvent for swelling the carrier, any solvent can be used as long as the carrier swells to such an extent that it can be used for peptide synthesis. Preferably, N, N-dimethylformamide (DMF) or dichloromethane is used. (DCM). The swollen carrier can be removed from the solvent by filtration or the like.
固相合成に用いるアミノ酸としては、主鎖のアミノ基が9−フルオレニルメチルカルボニル(Fmoc)基又はt−ブトキシカルボニル(Boc)基で保護されているものが好ましいが、これらに限られるものではない。ペプチド合成後の担体からの切り出しが容易という点で、主鎖のアミノ基がFmoc基で保護されたアミノ酸(以下、Fmoc−AA−OH、ただしAAは本発明のペプチド中のアミノ酸を示す、とも言う)が好ましい。またこの場合、アミノ酸の側鎖部位に、水酸基、チオール基、アミノ基、カルボキシル基等が存在する場合、これらの官能基はFmoc基及びBoc基以外の保護基で保護されることが好ましい。このような保護基の導入については、Green&Wuts, “PROTECTIVE GROUPS in ORGANIC SYNTHESIS” 3rded. John Wiley&Sons, Inc.を参照し、用いることができる。 As the amino acid used in the solid phase synthesis, those in which the amino group of the main chain is protected with a 9-fluorenylmethylcarbonyl (Fmoc) group or a t-butoxycarbonyl (Boc) group are preferable, but the amino acids are not limited thereto. is not. An amino acid in which the amino group of the main chain is protected with an Fmoc group (hereinafter referred to as Fmoc-AA-OH, where AA represents an amino acid in the peptide of the present invention, since it is easy to cleave from the carrier after peptide synthesis. Say) is preferred. In this case, when a hydroxyl group, a thiol group, an amino group, a carboxyl group or the like is present in the side chain site of the amino acid, these functional groups are preferably protected with a protecting group other than the Fmoc group and the Boc group. The introduction of such protecting groups, Green & Wuts, "PROTECTIVE GROUPS in ORGANIC SYNTHESIS" 3 rd ed. John Wiley & Sons, referring to Inc., can be used.
担体へのFmoc−Tyr−OHの導入は公知の方法で行うことができる。例えば、縮合剤としてカルボジイミド系縮合剤を用いる方法が挙げられる。前記カルボジイミド系縮合剤としてはジシクロヘキシルカルボジイミド(DCC)、ジイソプロピルカルボジイミド(DIPC)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(WSCI)等を挙げることができる。また、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩を用いる際は、中和のために等量若しくは少過剰のアミンを加える必要がある。前記アミンとしては、トリエチルアミン、トリブチルアミン、ヒューニッヒ塩基等の第三級アミンが好ましく用いられる。反応に用いる溶媒としては、担体へアミノ酸を導入することができる限りいかなる溶媒を用いても良いが、DCM、テトラヒドロフラン、トルエン等を用いることができ、好ましくはDCMである。反応は、0℃〜溶媒の沸点までの反応温度で行うことができ、室温で反応させることが好ましい。前記反応では、通常触媒を用いられ、該触媒としてはピリジン、4−ジメチルアミノピリジン、4−ピロリジノピリジン等を用いることができる。上記反応によりFmoc−Tyrが導入された担体は、ろ過等により溶媒中から取り出すことができる。 Introduction of Fmoc-Tyr-OH into the carrier can be performed by a known method. For example, the method of using a carbodiimide type condensing agent as a condensing agent is mentioned. Examples of the carbodiimide condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI), and the like. When 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used, it is necessary to add an equal amount or a small excess of amine for neutralization. As the amine, tertiary amines such as triethylamine, tributylamine, and Hunig base are preferably used. As a solvent used in the reaction, any solvent can be used as long as an amino acid can be introduced into a carrier. However, DCM, tetrahydrofuran, toluene and the like can be used, and DCM is preferable. The reaction can be performed at a reaction temperature from 0 ° C. to the boiling point of the solvent, and is preferably performed at room temperature. In the reaction, a catalyst is usually used, and as the catalyst, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine and the like can be used. The carrier into which Fmoc-Tyr has been introduced by the above reaction can be removed from the solvent by filtration or the like.
また、担体にFmoc−Tyrが導入されたもの又はBoc−Tyrが導入されたものは、市販のものをもちいてもよい。このような保護されたTyrが導入された担体は、渡辺化学工業株式会社、シグマアルドリッチ社等から購入することもできる。 In addition, a carrier having Fmoc-Tyr or Boc-Tyr introduced therein may be commercially available. The carrier into which such protected Tyr is introduced can also be purchased from Watanabe Chemical Co., Ltd., Sigma Aldrich Co., etc.
以下、Fmoc−Tyrが導入された担体を例に本発明のペプチドの一般的な合成法を説明する。 Hereinafter, a general method for synthesizing the peptide of the present invention will be described with reference to a carrier into which Fmoc-Tyr has been introduced.
<Fmocの除去>
Fmoc−Tyrが導入された担体を反応溶媒で膨潤させ、2級アミンを添加することによりFmoc基を除去することができる。反応の進行は、Fmoc基の除去により発生する二酸化炭素の泡で確認することができる。前記反応溶媒としてはDMFを用いることが好ましい。また、前記2級アミンとしては、通常ピペリジンが用いられるが、ピロリジン、ジエチルアミン、ジブチルアミン、ジイソプロピルアミン等を用いることもできる。上記反応は、0℃〜溶媒の沸点までの反応温度で行うことができ、室温で反応させることが好ましい。反応後の担体は、ろ過等により溶媒中から取り出すことができる。
<Removal of Fmoc>
The carrier having the Fmoc-Tyr introduced therein is swollen with a reaction solvent, and a secondary amine is added to remove the Fmoc group. The progress of the reaction can be confirmed by carbon dioxide bubbles generated by the removal of the Fmoc group. It is preferable to use DMF as the reaction solvent. As the secondary amine, piperidine is usually used, but pyrrolidine, diethylamine, dibutylamine, diisopropylamine and the like can also be used. The above reaction can be performed at a reaction temperature from 0 ° C. to the boiling point of the solvent, and is preferably performed at room temperature. The carrier after the reaction can be taken out from the solvent by filtration or the like.
<ペプチド鎖の伸長>
上記で得たFmocを除去したTyrが導入された担体を再度DMFに膨潤し、Fmoc−Arg−OH、縮合剤、ヒューニッヒ塩基を添加し、ペプチド鎖の伸長を行う。前記縮合剤としては、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート(HBTU)、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボラート(TBTU)、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボラート(TBTU)、1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシド ヘキサフルオロホスフェート(HATU)、1−ヒドロキシベンゾトリアゾール(HOBt)、1−ヒドロキシ−7−アザベンゾトリアゾール(HOAt)等を単独で又は混合して用いることができる。上記反応は、0℃〜溶媒の沸点までの反応温度で行うことができ、室温で反応させることが好ましい。ペプチド鎖の伸長は、Kaiser試験により確認することができ、反応後の担体は、ろ過等により溶媒中から取り出すことができる。
<Elongation of peptide chain>
The carrier introduced with Tyr from which Fmoc has been removed is swollen again in DMF, Fmoc-Arg-OH, a condensing agent, and a Hunig base are added, and the peptide chain is elongated. As the condensing agent, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), O- (benzotriazol-1-yl) -N , N, N ′, N′-tetramethyluronium tetrafluoroborate (TBTU), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate (TBTU), 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBt) 1-hydroxy-7-azabenzotriazole (HOAt) or the like can be used alone or in combination. The above reaction can be performed at a reaction temperature from 0 ° C. to the boiling point of the solvent, and is preferably performed at room temperature. The elongation of the peptide chain can be confirmed by a Kaiser test, and the carrier after the reaction can be taken out from the solvent by filtration or the like.
上記、Fmocの除去及びペプチド鎖の伸長を、順次Leu、Gly、Phe、Serについて行うことにより、化合物番号2に示すペプチド鎖に対応するペプチドを合成することができる。また、さらに、Fmocの除去及びペプチド鎖の伸長を、順次Asn、Trp、Asn、Tyrについて行うことにより、化合物番号1に示すペプチド鎖に対応するペプチドを合成することができる。 The peptide corresponding to the peptide chain shown in Compound No. 2 can be synthesized by sequentially removing Leo, Gly, Phe, and Ser in the above-described manner by removing Fmoc and extending the peptide chain. Further, by removing Fmoc and extending the peptide chain sequentially for Asn, Trp, Asn, and Tyr, a peptide corresponding to the peptide chain shown in Compound No. 1 can be synthesized.
合成したペプチド鎖は、担体からの切り出しの前にセリン残基の側鎖部位の水酸基をアシル化する。該アシル化に先立って、セリン残基の側鎖部位の水酸基の保護基を除去する。前記脱保護については、Green&Wuts, “PROTECTIVE GROUPS in ORGANIC SYNTHESIS” 3rded. John Wiley&Sons, Inc.を参照し、用いることができる。 The synthesized peptide chain acylates the hydroxyl group at the side chain site of the serine residue before excision from the carrier. Prior to the acylation, the hydroxyl protecting group at the side chain site of the serine residue is removed. Above for deprotection, Green & Wuts, "PROTECTIVE GROUPS in ORGANIC SYNTHESIS" 3 rd ed. John Wiley & Sons, referring to Inc., can be used.
前記アシル化のための反応は、脂肪酸を用いて公知の方法で行うことができる。前記脂肪酸は、RCOOH(Rは、上記で定めた通り。)である。 The reaction for the acylation can be performed by a known method using a fatty acid. The fatty acid is RCOOH (R is as defined above).
前記アシル化反応としては、例えば、縮合剤としてカルボジイミド系縮合剤を用いる方法が挙げられる。前記カルボジイミド系縮合剤としてはジシクロヘキシルカルボジイミド(DCC)、ジイソプロピルカルボジイミド(DIPC)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(WSCI)等を挙げることができる。また、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩を用いる際は、中和のために等量若しくは少過剰のアミンを加える必要がある。前記アミンとしては、トリエチルアミン、トリブチルアミン、ヒューニッヒ塩基等の第三級アミンが好ましく用いられる。反応に用いる溶媒としては、担体へアミノ酸を導入することができる限りいかなる溶媒を用いても良いが、DCM、テトラヒドロフラン、トルエン、ピリジン等を用いることができ、好ましくはDCMである。反応は、0℃〜溶媒の沸点までの反応温度で行うことができ、室温で反応させることが好ましい。前記反応では、通常触媒を用いられ、該触媒としてはピリジン、4−ジメチルアミノピリジン、4−ピロリジノピリジン等を用いることができる。上記反応によりアシル基が導入されたペプチドが結合した担体は、ろ過等により溶媒中から取り出すことができる。 Examples of the acylation reaction include a method using a carbodiimide condensing agent as a condensing agent. Examples of the carbodiimide condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI), and the like. When 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used, it is necessary to add an equal amount or a small excess of amine for neutralization. As the amine, tertiary amines such as triethylamine, tributylamine, and Hunig base are preferably used. As a solvent used in the reaction, any solvent can be used as long as an amino acid can be introduced into a carrier, but DCM, tetrahydrofuran, toluene, pyridine and the like can be used, and DCM is preferable. The reaction can be performed at a reaction temperature from 0 ° C. to the boiling point of the solvent, and is preferably performed at room temperature. In the reaction, a catalyst is usually used, and as the catalyst, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine and the like can be used. The carrier to which the peptide having an acyl group introduced by the above reaction is bound can be removed from the solvent by filtration or the like.
アシル化後のペプチドは、公知の方法で担体から切り出すことができる。例えば、ペプチドの切り出しはトリフルオロ酢酸等の強酸を用いて行う。この際、ペプチド中の各アミノ酸の側鎖の保護基の除去が同時に行われても良い。ペプチド中の各アミノ酸の側鎖の保護基の除去が同時に行われる場合、副反応を抑制する目的で、トリイソプロピルシラン及び/又はエタンジチオールを添加しても良い。ただし、切り出し後にC末端カルボン酸のアミド化を行う必要があるため、この時点でアミノ酸の側鎖のカルボン酸の保護基が除去されることは望ましくない。前記ペプチドの担体からの切り出しは、通常水中で行われ、反応温度は4℃〜室温が好ましい。
ペプチドをレジンから切り出した後に、ペプチドのC末端のカルボン酸の第1級アミド化を行う。前記アミド化は、公知の方法で行うことができるが、例えば、4−(4,6−ジメトキシ−1,3,5−トリアジン−2−イル)−4−メチルモルホリニウム 塩酸塩 n−水和物とアンモニアの溶液を用いる方法が挙げられる。前記、アンモニアの溶液としては、第1級アミドが製造される限り、いかなるアンモニア溶液を用いても構わないが、アンモニアのアルコール溶液を用いることが好ましい。
前記C末端のカルボン酸の第1級アミド化後に、必要であればペプチド中の各アミノ酸の保護基の除去を行う。前記保護基の除去については、Green&Wuts, “PROTECTIVE GROUPS in ORGANIC SYNTHESIS” 3rd ed. John Wiley&Sons, Inc.を参照し、用いることができる。
The acylated peptide can be excised from the carrier by a known method. For example, the peptide is cut out using a strong acid such as trifluoroacetic acid. At this time, removal of the protecting group on the side chain of each amino acid in the peptide may be performed simultaneously. When removal of the protecting group on the side chain of each amino acid in the peptide is performed simultaneously, triisopropylsilane and / or ethanedithiol may be added for the purpose of suppressing side reactions. However, since it is necessary to amidate the C-terminal carboxylic acid after excision, it is not desirable to remove the carboxylic acid protecting group on the side chain of the amino acid at this point. Cleavage of the peptide from the carrier is usually performed in water, and the reaction temperature is preferably 4 ° C. to room temperature.
After cleaving the peptide from the resin, primary amidation of the C-terminal carboxylic acid of the peptide is performed. The amidation can be performed by a known method. For example, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium hydrochloride n-water A method using a solution of a hydrate and ammonia is mentioned. As the ammonia solution, any ammonia solution may be used as long as the primary amide is produced, but an ammonia alcohol solution is preferably used.
After the primary amidation of the C-terminal carboxylic acid, the protecting group of each amino acid in the peptide is removed if necessary. The removal of the protecting group, Green & Wuts, "PROTECTIVE GROUPS in ORGANIC SYNTHESIS" 3 rd ed. John Wiley & Sons, referring to Inc., can be used.
本発明のペプチド誘導体の塩としては、薬理学的に許容される有機酸塩、金属塩、アンモニウム塩、有機アミン付加塩などが挙げられる。 Examples of the salt of the peptide derivative of the present invention include pharmacologically acceptable organic acid salts, metal salts, ammonium salts, and organic amine addition salts.
上記本発明のペプチド誘導体の有機酸塩としては、具体的には酢酸塩、2,2−ジクロロ酢酸塩、トリフルオロ酢酸塩、アシル化したアミノ酸の塩、アジピン酸塩、アルギン酸塩、アスコルビン酸塩、L−アスパラギン酸塩、ベンゼンスルホン酸塩、安息香酸塩、4−アセトアミド安息香酸塩、ホウ酸塩、(+)−ショウノウ酸塩、カンファースルホン酸塩、カプリン酸塩、カプロン酸塩、カプリル酸塩、ケイ皮酸塩、クエン酸塩、シクラミン酸塩、シクロヘキサンスルファミン酸塩、ドデシル硫酸塩、エタン−1,2−ジスルホン酸塩、エタンスルホン酸塩、2−ヒドロキシ−エタンスルホン酸塩、ギ酸塩、フマル酸塩、ガラクタル酸塩、ゲンチシン酸塩、グルコヘプトン酸塩、D−グルコン酸塩、D−グルクロン酸塩、L−グルタミン酸塩、α−オキソグルタル酸塩、グリコール酸塩、馬尿酸塩、臭化水素酸塩、塩酸塩、ヨウ化水素塩酸、(+)−L−乳酸塩、(±)−DL−乳酸塩、ラクトビオン酸塩、ラウリン酸塩、マレイン酸塩、(−)−L−リンゴ酸塩、マロン酸塩、(±)−DL−マンデル酸塩、メタンスルホン酸塩、ナフタレン−2−スルホン酸塩、ナフタレン−1,5−ジスルホン酸塩、1−ヒドロキシ−2−ナフトエ酸塩、ニコチン酸塩、硝酸塩、オレイン酸塩、オロト酸塩、シュウ酸塩、パルミチン酸塩、パモ酸塩、過塩素酸塩、リン酸塩、L−ピログルタミン酸塩、サッカリン酸塩、サリチル酸塩、4−アミノサリチル酸塩、セバシン酸塩、ステアリン酸塩、コハク酸塩、硫酸塩、タンニン酸塩、(+)−L−酒石酸塩、チオシアン酸塩、p−トルエンスルホン酸塩、ウンデシレン酸塩、吉草酸等塩が挙げられる。 Specific examples of the organic acid salt of the peptide derivative of the present invention include acetate, 2,2-dichloroacetate, trifluoroacetate, acylated amino acid salt, adipate, alginate, and ascorbate. , L-aspartate, benzenesulfonate, benzoate, 4-acetamidobenzoate, borate, (+)-camphorate, camphorsulfonate, caprate, caproate, caprylic acid Salt, cinnamate, citrate, cyclamate, cyclohexanesulfamate, dodecyl sulfate, ethane-1,2-disulfonate, ethanesulfonate, 2-hydroxy-ethanesulfonate, formate , Fumarate, galactate, gentisate, glucoheptonate, D-gluconate, D-glucuronate, L-glutamic acid , Α-oxoglutarate, glycolate, hippurate, hydrobromide, hydrochloride, hydroiodide hydrochloride, (+)-L-lactate, (±) -DL-lactate, lactobionate , Laurate, maleate, (−)-L-malate, malonate, (±) -DL-mandelate, methanesulfonate, naphthalene-2-sulfonate, naphthalene-1, 5-disulfonate, 1-hydroxy-2-naphthoate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate, perchlorate, phosphate , L-pyroglutamate, saccharinate, salicylate, 4-aminosalicylate, sebacate, stearate, succinate, sulfate, tannate, (+)-L-tartrate, thiocyanic acid Salt, p-toluenesulfur Emissions salt, undecylenic acid salts, and valerate salts, etc..
上記有機酸塩の他にも、本発明のペプチド誘導体の塩としては、リチウム、ナトリウム、カリウムなどの各アルカリ金属塩、マグネシウム、カルシウムなどの各アルカリ土類金属塩、アルミニウム、亜鉛などの各金属塩;L−アルギニン、ベネタミン、ベンザチン、コリン、デアノール、ジエタノールアミン、ジエチルアミン、ジメチルアミン、ジプロピルアミン、ジイソプロピルアミン、2−(ジエチルアミノ)−エタノール、エタノールアミン、エチルアミン、エチレンジアミン、イソプロピルアミン、N−メチル−グルカミン、ヒドラバミン、1H−イミダゾール、L−リジン、モルフォリン、4−(2−ヒドロキシエチル)−モルフォリン、メチルアミン、ピペリジン、ピペラジン、プロピルアミン、ピロリジン、1−(2−ヒドロキシエチル)−ピロリジン、ピリジン、キヌクリジン、キノリン、イソキノリン、トリエタノールアミン、トリメチルアミン、トリエチルアミン、N−メチル−D−グルカミン、2−アミノ−2−(ヒドロキシメチル)−1,3−プロパンジオール、及びトロメタミンを含む、第一級、第二級、第三級、若しくは第四級の脂肪族又は芳香族アミンの塩が挙げられる。 In addition to the above organic acid salts, examples of the salt of the peptide derivative of the present invention include alkali metal salts such as lithium, sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and metals such as aluminum and zinc. Salt: L-arginine, venetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl- Glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2-hydro Ciethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1,3-propanediol, and tromethamine Including salts of primary, secondary, tertiary, or quaternary aliphatic or aromatic amines.
本発明の医薬の有効成分としては、化合物番号1及び/又は化合物番号2で表される化合物の溶媒和物や結晶多形も含まれる。ここで溶媒和物とは、非共有結合分子間力によって結合した化学量論的又は非化学量論的な量の溶媒をさらに含む、本発明の化合物又はその塩を指す。溶媒が水である場合、溶媒和物は水和物である。 The active ingredient of the medicament of the present invention also includes solvates and crystal polymorphs of the compound represented by Compound No. 1 and / or Compound No. 2. A solvate as used herein refers to a compound of the present invention or a salt thereof further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.
本発明の医薬は、当業者に公知の方法で製剤化することができる。例えば、薬学的に許容しうる担体もしくは媒体、具体的には、滅菌水や生理食塩水、植物油、乳化剤、懸濁剤、界面活性剤、安定剤、香味剤、賦形剤、防腐剤、結合剤などと適宜組み合わせて、一般に認められた製薬実施に要求される単位用量形態で混和することによって製剤化された、医薬組成物であってもよい。 The medicament of the present invention can be formulated by methods known to those skilled in the art. For example, a pharmaceutically acceptable carrier or vehicle, specifically, sterile water or saline, vegetable oil, emulsifier, suspension, surfactant, stabilizer, flavoring agent, excipient, preservative, binding It may be a pharmaceutical composition formulated by mixing in an appropriate combination with an agent and the like in a unit dosage form generally required for pharmaceutical practice.
前記医薬組成物において、経口投与用としては、本発明の医薬を当該技術分野においてよく知られる薬学的に許容しうる担体と混合することにより、錠剤、丸薬、糖衣剤、カプセル、液体、ゲル、シロップ、スラリー、懸濁液などとして処方することができる。担体としては、当該技術分野において公知のものを広く使用することができ、例えば、乳糖、白糖、塩化ナトリウム、グルコース、尿素、澱粉、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸などの賦形剤;水、エタノール、プロパノール、単シロップ、グルコース液、澱粉液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドンなどの結合剤、乾燥澱粉、アルギン酸ナトリウム、寒天末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、澱粉、乳糖などの崩壊剤;白糖、ステアリン、カカオバター、水素添加油などの崩壊抑制剤;第4級アンモニウム塩類、ラウリル硫酸ナトリウムなどの吸収促進剤;グリセリン、澱粉などの保湿剤;澱粉、乳糖、カオリン、ベントナイト、コロイド状ケイ酸などの吸着剤;精製タルク、ステアリン酸塩、ホウ酸末、ポリエチレングリコールなどの潤沢剤などを用いることができる。さらに錠剤は、必要に応じ、通常の剤皮を施した錠剤、例えば、糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠、あるいは二重錠、多層錠とすることができる。 In the above pharmaceutical composition, for oral administration, the pharmaceutical of the present invention is mixed with a pharmaceutically acceptable carrier well known in the art, whereby tablets, pills, dragees, capsules, liquids, gels, It can be formulated as a syrup, slurry, suspension or the like. As the carrier, those known in the art can be widely used. For example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, bicarbonate Disintegrating agents such as sodium, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts Absorption promoters such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; purified talc, stearate, boric acid powder, polyethylene glycol, etc. A lubricant can be used. Furthermore, the tablet can be a tablet coated with a normal coating, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet, if necessary.
前記医薬組成物において、非経口投与用としては、本発明の医薬を当該技術分野においてよく知られる薬学的に許容しうる賦形剤を用いて通常の製剤実施に従って処方することができる。 In the above pharmaceutical composition, for parenteral administration, the medicament of the present invention can be formulated according to usual pharmaceutical practice using pharmaceutically acceptable excipients well known in the art.
注射剤用の水溶性賦形剤としては、例えば生理食塩水、ブドウ糖やその他の補助薬を含む等張液、例えばD−ソルビトール、D−マンノース、D−マンニトール、塩化ナトリウムが挙げられ、適当な溶解補助剤、例えばアルコール、具体的にはエタノール、ポリアルコール、例えばプロピレングリコール、ポリエチレングリコール、非イオン性界面活性剤、例えばポリソルベート80(TM)、HCO−50と併用してもよい。 Examples of water-soluble excipients for injection include isotonic solutions containing physiological saline, glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol and sodium chloride. It may be used in combination with a solubilizer such as alcohol, specifically ethanol, polyalcohol such as propylene glycol, polyethylene glycol, nonionic surfactant such as polysorbate 80 (TM), HCO-50.
油性賦形剤としてはゴマ油、大豆油があげられ、溶解補助剤として安息香酸ベンジル、ベンジルアルコールと併用してもよい。また、緩衝剤、例えばリン酸塩緩衝液、酢酸ナトリウム緩衝液、無痛化剤、例えば、塩酸プロカイン、安定剤、例えばベンジルアルコール、フェノール、酸化防止剤と配合してもよい。調製された注射液は通常、適当なアンプルに充填させる。 Oily excipients include sesame oil and soybean oil, which may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizer. Moreover, you may mix | blend with buffer, for example, phosphate buffer, sodium acetate buffer, a soothing agent, for example, procaine hydrochloride, stabilizer, for example, benzyl alcohol, phenol, antioxidant. The prepared injection solution is usually filled into a suitable ampoule.
また、本発明の医薬の分散を制御するなどの目的で、担体、例えば、コラーゲン、ハイドロキシアパタイト、ヒアルロン酸、フィブリン、多糖、リポゾームと配合してもよい。調製された製剤は、経口剤または非経口投与剤として使用できる。 In addition, for the purpose of controlling the dispersion of the medicament of the present invention, it may be blended with a carrier such as collagen, hydroxyapatite, hyaluronic acid, fibrin, polysaccharide, or liposome. The prepared preparation can be used as an oral preparation or a parenteral administration preparation.
(投与形態)
本発明の医薬の適当な投与経路としては特に限定されず、経口、直腸内、経粘膜、または腸内、または筋肉内、皮下、骨髄内、鞘内、直接心室内、静脈内、硝子体内、腹腔内、鼻腔内、または眼内注射が含まれる。投与経路は、患者/患畜の年齢や病状、併用する他の薬剤などを考慮して適宜選択することができる。
(Dosage form)
The administration route of the medicament of the present invention is not particularly limited, and is oral, rectal, transmucosal, or intestinal, or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, Intraperitoneal, intranasal, or intraocular injection is included. The administration route can be appropriately selected in consideration of the age and medical condition of the patient / patient, other drugs used in combination.
本発明の医薬の投与量としては、性腺刺激ホルモン放出ホルモン及び黄体形成ホルモンを分泌促進しうる量であればよく、投与方法、年齢、症状等により適宜決定することができる。例えば、前記有効成分の質量に基づき、一回につき体重1kgあたり0.001mg〜1mg、また好ましくは患者/患畜あたり1回投与あたり0.002〜100mgである。 The dosage of the medicament of the present invention may be an amount that can promote secretion of the gonadotropin-releasing hormone and luteinizing hormone, and can be appropriately determined depending on the administration method, age, symptoms, and the like. For example, based on the mass of the active ingredient, it is 0.001 mg to 1 mg per kg body weight per dose, and preferably 0.002 to 100 mg per dose per patient / patient.
本発明において、Tyr−Asn−Trp−Asn−Ser−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号3)をキスペプチン10、すなわちKP10と表記し、Ser−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号4)をキスペプチン6、すなわちKP6と表記する。後述する実施例において、KP10のN末端のTyrの位置を1位、C末端のTyrの位置を10位と数え、KP6のN末端のSerの位置を1位、C末端のTyrの位置を6位と数える。また、化合物番号5(実施例1)の[dY]KP10はKP10のN末端(1位)のTyrがD体(右旋性)であることを意味し、化合物番号6(実施例1)の[dS]KP6はKP6のN末端(1位)のSerがD体(右旋性)であることを意味する。化合物番号7(実施例1)のAc−KP10及び化合物番号8(実施例1)のAc−KP6は、KP10及びKP6のN末端(1位)アミノ酸のアミノ基がアセチル化していることを意味する。さらに、化合物番号9(実施例1)のオクタン酸側鎖付KP10及び、化合物番号10(実施例1)のオクタン酸側鎖付KP6は、KP10及びKP6のC末端から数えて6位のSerがn−オクタノイル化されていることを意味する。 In the present invention, is denoted by Tyr-Asn-Trp-Asn- Ser-Phe-Gly-Leu-Arg-Tyr-NH 2 ( Compound No. 3) The Kisspeptin 10, i.e. KP10, Ser-Phe-Gly- Leu-Arg -Tyr-NH 2 (compound No. 4) kisspeptin 6, i.e. is expressed as KP6. In the examples described later, the position of the N-terminal Tyr of KP10 is counted as position 1, the position of the C-terminal Tyr is counted as position 10, the position of the N-terminal Ser of KP6 is position 1, and the position of the C-terminal Tyr is 6 Count as a place. [DY] KP10 of Compound No. 5 (Example 1) means that Tyr at the N-terminus (position 1) of KP10 is D-form (dextrorotatory), and that of Compound No. 6 (Example 1) [DS] KP6 means that Ser at the N-terminus (position 1) of KP6 is D-form (dextrorotatory). Ac-KP10 of Compound No. 7 (Example 1) and Ac-KP6 of Compound No. 8 (Example 1) mean that the amino group of the N-terminal (position 1) amino acid of KP10 and KP6 is acetylated. . Furthermore, KP10 with an octanoic acid side chain of Compound No. 9 (Example 1) and KP6 with an octanoic acid side chain of Compound No. 10 (Example 1) have Ser at the 6-position counted from the C-terminal of KP10 and KP6. It means being n-octanoylated.
以下、実施例により本発明をより詳細に説明するが、本発明の技術的範囲はこれらの例示に限定されるものではない。以下の実施例は全て、日本生理学会が定める生理学領域における動物実験に関する基本的指針に則り、国立大学法人山口大学共同獣医学部における動物実験倫理委員会の認可を得て行った。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, the technical scope of this invention is not limited to these illustrations. All of the following examples were conducted with the approval of the Animal Experimentation Ethics Committee at the Yamaguchi University Joint Veterinary Medicine, in accordance with the basic guidelines for animal experiments in the physiological field established by the Physiological Society of Japan.
1.ウシ脳下垂体前葉細胞の調製
ウシ脳下垂体前葉は、黒毛和牛雌(26か月齢)より、2011年9月から2012年7月の期間に得た。ウシ脳下垂体前葉組織を酵素法により単一細胞化し、単一化した細胞の生細胞率は、トリパンブルー染色により90%以上であることを確認してその後の実験に用いた。単一化した細胞は、1%非必須アミノ酸(100×; Gibco, Grand Island, NY, USA)、100 IU/mLペニシリン、50 μg/mLストレプトマイシン、10%ウマ血清(Gibco, Grand Island, NY, USA)、2.5%ウシ胎児血清(Gibco, Grand Island, NY, USA)を加えたダルベッコ改変イーグル培地(DMEM; Gibco, Grand Island, NY, USA)に懸濁した。2.5×105細胞/mLの濃度に調製した細胞を、24ウェルプレート(MS-80240;住友ベークイライト、東京、日本)上で、37℃、5%二酸化炭素、湿潤条件下において82時間培養した。
1. Preparation of bovine pituitary cells Bovine pituitary cells were obtained from Japanese black cows (26 months old) from September 2011 to July 2012. The anterior bovine pituitary tissue was made into a single cell by the enzyme method, and the viable cell rate of the unified cell was confirmed to be 90% or more by trypan blue staining, and used in the subsequent experiments. Uniformized cells consist of 1% non-essential amino acids (100 ×; Gibco, Grand Island, NY, USA), 100 IU / mL penicillin, 50 μg / mL streptomycin, 10% horse serum (Gibco, Grand Island, NY, USA) and 2.5% fetal bovine serum (Gibco, Grand Island, NY, USA) and suspended in Dulbecco's modified Eagle medium (DMEM; Gibco, Grand Island, NY, USA). Cells prepared at a concentration of 2.5 × 10 5 cells / mL were placed on a 24-well plate (MS-80240; Sumitomo Bakelite, Tokyo, Japan) for 82 hours at 37 ° C., 5% carbon dioxide, in humid conditions. Cultured.
2.ペプチドの合成
化合物番号9及び化合物番号10で表されるペプチド誘導体は、P. Robberecht et. al. Mol. Phrmacol. 42, 347-355 (1992)に記載の方法を参考に合成した。
すなわち、AMレジンの一つである4−(2’,4’−ジメトキシフェニル−Fmoc−アミノメチル)−フェノキシレジンを固相担体とし、ペプチドの合成を行った。まず、前記固相担体にFmoc-Tyr−OHを結合し、順次Focの除去、ペプチド伸長を繰り返し、Arg、Leu、Gly、Phe、Ser、Asn、Trp、Asn、Tyrをペプチド鎖に組み込みながら伸長し、Tyr−Asn−Trp−Asn−Ser−Phe−Gly−Leu−Arg−Tyrからなるペプチドを合成した。ペプチド伸長は、HOBt及びHBTUを用いた。続いて、ペプチド中の各アミノ酸の側鎖の保護基のうち、Ser側鎖の水酸基の保護基であるトリフェニルメチル基(トリチル基)を、1%トリフルオロ酢酸を用いて除去した。前記保護基の除去後のSer側鎖の水酸基に、オクタン酸及びWSCIを作用させることで、選択的にアシル化を行った。アシル化後のペプチドはトリフルオロメタンスルホン酸を用いて担体から切り出され、C末端のカルボン酸を第1級アミドへと変換した後に、HPLCで生成を行った。得られた化合物番号9で表されるペプチド誘導体は、質量分析において1445(M+1)+のピークを示し、その計算値と一致した。
上記手法と同様の方法により、化合物番号10で表されるペプチド誘導体を合成した、得られたペプチド誘導体は、質量分析において868(M+1)+のピークを示し、その計算値と一致した。
2. Peptide Synthesis The peptide derivatives represented by Compound No. 9 and Compound No. 10 were synthesized with reference to the method described in P. Robberecht et. Al. Mol. Phrmacol. 42, 347-355 (1992).
That is, peptide synthesis was performed using 4- (2 ′, 4′-dimethoxyphenyl-Fmoc-aminomethyl) -phenoxyresin, which is one of AM resins, as a solid support. First, Fmoc-Tyr-OH is bound to the solid phase carrier, and Foc removal and peptide elongation are repeated sequentially, and Arg, Leu, Gly, Phe, Ser, Asn, Trp, Asn, and Tyr are extended while being incorporated into the peptide chain. Then, a peptide composed of Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Tyr was synthesized. Peptide extension used HOBt and HBTU. Subsequently, among the protecting groups on the side chain of each amino acid in the peptide, the triphenylmethyl group (trityl group), which is a protecting group for the hydroxyl group on the Ser side chain, was removed using 1% trifluoroacetic acid. The acylation was selectively carried out by allowing octanoic acid and WSCI to act on the hydroxyl group of the Ser side chain after removal of the protecting group. The acylated peptide was cleaved from the support using trifluoromethanesulfonic acid, and the C-terminal carboxylic acid was converted to a primary amide, followed by generation by HPLC. The obtained peptide derivative represented by Compound No. 9 showed a peak of 1445 (M + 1) + in mass spectrometry, which was consistent with the calculated value.
The peptide derivative obtained by synthesizing the peptide derivative represented by Compound No. 10 by the same method as that described above showed a peak of 868 (M + 1) + in mass spectrometry, which was consistent with the calculated value.
3.各化合物による培養ウシ下垂体前葉細胞の刺激
黒毛和牛雌(n=16)より得た脳下垂体前葉細胞を82時間培養後、リン酸緩衝生理食塩水(PBS)にて2度洗浄した。その後、0.1%ウシ血清アルブミン(BSA; protease-free grade, 01862-87;ナカライテスク、京都、日本)加DMEMのみ、10nM(1x10−8M)GnRH(株式会社ペプチド研究所、大阪、日本)を含む0.1%BSA加DMEM、10nM(1x10−8M)、100nM(1x10−7M)、1000nM(1x10−6M)、10,000nM(1x10−5M)の各濃度の、KP10(化合物番号3)、[dY]KP10(化合物番号5)、[dS]KP6(化合物番号6)、Ac−KP10(化合物番号7)、Ac−KP6(化合物番号8)、オクタン酸側鎖付KP10(化合物番号9)、オクタン酸側鎖付KP6(化合物番号10)をそれぞれ含む0.1%BSA加DMEMで、脳下垂体前葉細胞の培養液を交換した。前記キスペプチン誘導体は、上記方法により合成され(株式会社スクラム、東京、日本)、高速液体クロマトグラフィー及び質量分析法で確認された高純度ものを使用した。各化合物との刺激開始から2時間後、培養液を回収し、ウシLH濃度測定まで‐30℃で保管した。
3. Stimulation of cultured bovine pituitary cells by each compound Pituitary anterior pituitary cells obtained from Japanese black cows (n = 16) were cultured for 82 hours and then washed twice with phosphate buffered saline (PBS). Thereafter, 0.1% bovine serum albumin (BSA; protease-free grade, 01862-87; Nacalai Tesque, Kyoto, Japan) plus DMEM only, 10 nM (1 × 10 −8 M) GnRH (Peptide Institute, Osaka, Japan) ) With 0.1% BSA added DMEM, 10 nM (1 × 10 −8 M), 100 nM (1 × 10 −7 M), 1000 nM (1 × 10 −6 M), 10,000 nM (1 × 10 −5 M), KP10 (Compound No. 3), [dY] KP10 (Compound No. 5), [dS] KP6 (Compound No. 6), Ac-KP10 (Compound No. 7), Ac-KP6 (Compound No. 8), KP10 with octanoic acid side chain The culture solution of anterior pituitary cells was exchanged with 0.1% BSA-added DMEM containing (Compound No. 9) and KP6 with octanoic acid side chain (Compound No. 10). The kisspeptin derivative was synthesized by the above method (Scrum Co., Ltd., Tokyo, Japan), and the high purity one confirmed by high performance liquid chromatography and mass spectrometry was used. Two hours after the start of stimulation with each compound, the culture solution was collected and stored at −30 ° C. until the measurement of bovine LH concentration.
4.培養ウシ下垂体前葉細胞からのLH分泌量を指標としたキスペプチン活性評価
上記で回収した培養液中のLH濃度は、125I標識ウシLH及び抗ヒツジLH抗血清 (AFP11743B,AFP192279; National Hormone and Pituitary Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, CA, USA)を用いた二抗体ラジオイムノアッセイにて二重測定した。検出限界値は0.40ng/mLであった。また、2.04ng/mLにおいて、測定内変動係数は3.6%、測定間変動係数は6.2%であった。培養液のみを下垂体前葉細胞に添加したControl培養液中LH濃度に対する、各化合物を添加した培養液中LH濃度の比率を求めたところ、オクタン酸側鎖付KP10(化合物番号9)及びオクタン酸側鎖付KP6(化合物番号10)の添加による刺激では、添加濃度の差がLH濃度の比率差に現れず(図1)、また、KP10のLH濃度比率に対し、約2倍のLH分泌を誘導することが明らかとなった。
4). Evaluation of kisspeptin activity using LH secretion from cultured bovine anterior pituitary cells as an index The LH concentration in the culture medium recovered above is 125 I-labeled bovine LH and anti-sheep LH antiserum (AFP11743B, AFP192279; National Hormone and Pituitary Double measurement was performed by a two-antibody radioimmunoassay using the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, CA, USA. The detection limit value was 0.40 ng / mL. At 2.04 ng / mL, the coefficient of variation within measurement was 3.6%, and the coefficient of variation between measurements was 6.2%. When the ratio of the LH concentration in the culture solution added with each compound to the LH concentration in the Control culture solution in which only the culture solution was added to the anterior pituitary cells was determined, KP10 with an octanoic acid side chain (compound number 9) and octanoic acid were obtained. In the stimulation by the addition of side chain-attached KP6 (Compound No. 10), the difference in the addition concentration does not appear in the LH concentration ratio difference (FIG. 1), and the LH secretion is about twice as high as the LH concentration ratio of KP10. It became clear to induce.
本発明は、家畜の繁殖における発情同期化・過排卵処置に好適に利用することができる、優れたホルモン製剤として、また、ホルモン感受性癌の予防・治療及び転移抑制剤として有用性を発揮しうると期待される。
INDUSTRIAL APPLICABILITY The present invention can be used as an excellent hormone preparation that can be suitably used for estrus synchronization / superovulation treatment in livestock breeding, and can also be useful as a prophylactic / therapeutic agent for hormone-sensitive cancer and as a metastasis inhibitor. It is expected.
Claims (5)
(b)Ser−Phe−Gly−Leu−Arg−Tyr−NH 2 (化合物番号4)のC末端から数えて6位のSerがn−オクタノイル化されたペプチド誘導体;
から選択されるペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。 (A) Tyr-Asn-Trp -Asn-Ser-Phe-Gly-Leu-Arg-Tyr-NH 2 peptide derivatives counted from the C-terminal 6-position of the Ser is n- octanoyl of (Compound No. 3);
(B) a peptide derivative in which Ser at position 6 is n-octanoylated from the C-terminus of Ser-Phe-Gly-Leu-Arg-Tyr-NH 2 (Compound No. 4);
Peptide derivative selected pressurized et al, or a salt or solvate thereof.
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