N6Rvm74spt | 214487-46-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N6Rvm74spt
• 英文别名: N-[(1S,2R)-2-[[(2R)-2-[methyl-[2-(4-methylphenyl)acetyl]amino]-3-naphthalen-2-ylpropanoyl]amino]cyclohexyl]-1H-indole-3-carboxamide
• CAS: 214487-46-4
• 化学式: C₃₈H₄₀N₄O₃
• 分子量: 600.7
• InChiKey: JXDKAWGCUBTYFX-BMPTZRATSA-N

物化性质

• 沸点：
  926.8±65.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  45
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  94.3
• 氢给体数：
  3
• 氢受体数：
  3

制备方法与用途

生物活性

MEN11467 是一种有效的选择性拟肽速激肽 NK 1 受体拮抗剂。

靶点

Tachykinin NK ₁ receptor

体外研究

MEN11467 potently inhibits the binding of [ ³ H] substance P (SP) to tachykinin NK ₁ receptors in the IM9 limphoblastoid cell line (pK _i =9.4±0.1). MEN11467 is highly specific for the human tachykinin NK ₁ receptors, since it has negligible effects (pK _i <6) on the binding of specific ligands to tachykinin NK ₂ or NK ₃ receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN11467 at tachykinin NK ₁ receptors is insurmountable in saturation binding experiments, both K _D and B _max of SP are significantly reduced by MEN11467 (0.3-10 nM). In the guinea-pig isolated ileum, MEN11467 (0.03-1 nM) produces a nonparallel rightward shift of the concentration-response curve to SP methylester with a concomitant reduction of the E _max to the agonist (pK _B =10.7±0.1). Moreover the antagonist activity of MEN11467 is hardly reversible despite prolonged washout. The pseudopeptide tachykinin NK ₁ receptor antagonist, MEN11467 is used to study tachykininergic involvement in antigen-induced mucus secretion in ferret trachea in vitro. MEN11467 (1 nM-10 μM) inhibits [Sar ⁹ ]SP-induced ³⁵ SO ₄ , output in a concentration-dependent manner with an approximate IC ₅₀ of 0.3  μM.

体内研究

MEN11467 produces a long lasting (>2-3 h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK ₁ receptor agonist, [Sar ⁹ , Met(O ₂ ) ¹¹ ]SP in anaesthetized guinea-pigs (ID ₅₀ s=29±5, 31±12 and 670±270 μg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN11467 produces a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar ⁹ , Met(O ₂ ) ¹¹ ] (ID ₅₀ = 6.7±2 mg/kg) or by antigen challenge in sensitized animals (ID ₅₀ =1.3 mg/kg). After i.v. administration MEN11467 weakly inhibits the GR 73632-induced foot tapping behaviour in gerbil (ED ₅₀ =2.96±2 mg/kg), indicating a poor ability to block central tachykinin NK ₁ receptors. Treatment with MEN11467 (1 mmol/kg twice weekly for 2 weeks) results in a temporary growth arrest of the U373 MG xenograft that last for about 10 days until the last MEN11467 administration (TVI%=56). Thereafter, the tumor start to regrow. MEN11467 anti-tumor activity is partially reverted by the simultaneous administration of an equimolar dose of exogenous substance P (SP), suggesting the specificity of tachykinin NK1 receptor activation in glioma growth. Prolonged s.c. treatment with a higher MEN11467 dose (1.7 mmol/kg at five times a week for 6 weeks) completely inhibits the growth of U373 MG tumor for the entire length of the experiment, even following administration of a low exogenous SP dose. After 6 weeks, the tumor mass is not increased compared to the untreated control with TVI%=96%.

文献信息

• NOVEL TETRAHYDROCARBAZOLE DERIVATIVES AS LIGANDS OF G-PROTEIN COUPLED RECEPTORS
  申请人：SCHUSTER Tilmann

  公开号：US20120122763A1

  公开（公告）日：2012-05-17

  The present invention provides novel tetrahydrocarbazole compounds according to formula (I) as ligands of G-protein coupled receptors (GPCR) which are useful in the treatment and/or prophylaxis of physiological and/or pathological conditions in mammals mediated by GPCR or of physiological and/or pathological conditions which can be treated by modulation of these receptors.

  本发明提供了新型四氢咔唑化合物，其符合公式（I），作为G蛋白偶联受体（GPCR）的配体，可用于治疗和/或预防哺乳动物由GPCR介导的生理和/或病理状况，或可以通过调节这些受体来治疗的生理和/或病理状况。
• Novel Tetrahydrocarbazole Derivatives as Ligands of G-protein Coupled Receptors
  申请人：Æterna Zentaris GmbH

  公开号：EP1988098A1

  公开（公告）日：2008-11-05

  The present invention provides novel tetrahydrocarbazole derivatives according to formula (I) as ligands of G-protein coupled receptors (GPCR). The compounds of the invention are useful in the treatment and/or prophylaxis of physiological and/or pathological conditions in mammals, preferably humans, which are mediated by GPCR or of physiological and/or pathological conditions which can be treated by modulation of these receptors. The present invention further provides LHRH receptor antagonists that can be used for the modulation of these receptors and are useful for treating above conditions, in particular prostate cancer, breast cancer, uterine cancer, endometrial cancer, cervical cancer, ovarian cancer, benign prostate hyperplasia (BPH), endometriosis, uterine fibroids, uterine myomas, endometrium hyperplasia, dysmenorrhoea, dysfunctional uterine bleeding (menorrhagia, metrorrhagia), pubertas praecox, hirsutism, polycystic ovary syndrome, hormone-dependent tumor diseases, HIV infections or AIDS, neurological or neurodegenerative disorders, ARC (AIDS related complex), Kaposi sarcoma, tumors originating from the brain and/or nervous system and/or meninges, dementia, Alzheimer's disease, nausea and vomiting, pain, inflammations, rheumatic and arthritic pathological states.

  本发明提供了公式（I）的新型四氢咔唑衍生物，作为G蛋白偶联受体（GPCR）的配体。本发明的化合物可用于治疗和/或预防哺乳动物，尤其是人类的生理和/或病理状况，这些状况是由GPCR介导的或可以通过调节这些受体来治疗的生理和/或病理状况。本发明还提供了LHRH受体拮抗剂，可用于调节这些受体，对于治疗上述疾病，特别是前列腺癌、乳腺癌、子宫癌、子宫内膜癌、宫颈癌、卵巢癌、良性前列腺增生（BPH）、子宫内膜异位症、子宫肌瘤、子宫内膜增生、痛经、功能性子宫出血（月经过多、子宫出血）、早发性青春期、多毛症、多囊卵巢综合征、激素依赖性肿瘤疾病、HIV感染或艾滋病、神经或神经退行性疾病、ARC（艾滋病相关综合征）、卡波西肉瘤、起源于大脑和/或神经系统和/或脑膜的肿瘤、痴呆症、阿尔茨海默病、恶心和呕吐、疼痛、炎症、风湿和关节病理状态都很有用。
• US8148546B2
  申请人：——

  公开号：US8148546B2

  公开（公告）日：2012-04-03
• US8541462B2
  申请人：——

  公开号：US8541462B2

  公开（公告）日：2013-09-24
• [EN] NOVEL TETRAHYDROCARBAZOLE DERIVATIVES AS LIGANDS OF G-PROTEIN COUPLED RECEPTORS<br/>[FR] NOUVEAUX DÉRIVÉS DE TÉTRAHYDROCARBAZOLE EN TANT QUE LIGANDS DES RÉCEPTEURS COUPLÉS AUX PROTÉINES G
  申请人：AETERNA ZENTARIS GMBH

  公开号：WO2008132153A1

  公开（公告）日：2008-11-06

  [EN] The present invention provides novel tetrahydrocarbazole derivatives according to formula (I) as ligands of G-protein coupled receptors (GPCR). The compounds of the invention are useful in the treatment and/or prophylaxis of physiological and/or pathological conditions in mammals, preferably humans, which are mediated by GPCR or of physiological and/or pathological conditions which can be treated by modulation of these receptors. The present invention further provides LHRH receptor antagonists that can used for the modulation of these receptors and are useful for treating above conditions, in particular prostate cancer, breast cancer, uterine cancer, endometrial cancer, cervical cancer, ovarian cancer, benign prostate hyperplasia (BPH)1 endometriosis, uterine fibroids, uterine myomas, endometrium hyperplasia, dysmenorrhoea, dysfunctional uterine bleeding (menorrhagia, metrorrhagia), pubertas praecox, hirsutism, polycystic ovary syndrome, hormone-dependent tumor diseases, HIV infections or AIDS, neurological or neurodegenerative disorders, ARC (AIDS related complex), Kaposi sarcoma, tumors originating from the brain and/or nervous system and/or meninges, dementia, Alzheimer's disease, nausea and vomiting, pain, inflammations, rheumatic and arthritic pathological states.
  [FR] La présente invention concerne de nouveaux dérivés de tétrahydrocarbazole selon la formule (I) en tant que ligands des récepteurs couplés aux protéines G (RCPG). Les composés de l'invention sont utiles dans le traitement et/ou la prophylaxie d'affections physiologiques et/ou pathologiques chez des mammifères, de préférence des êtres humains, qui sont médiées par les RCPG ou d'affections physiologiques et/ou pathologiques qui peuvent être traitées par la modulation de ces récepteurs. La présente invention concerne en outre des antagonistes des récepteurs de la LHRH qui peuvent être utilisés pour la modulation de ces récepteurs et sont utiles pour le traitement des affections citées ci-dessus, en particulier un cancer de la prostate, un cancer du sein, un cancer de l'utérus, un cancer de l'endomètre, un cancer du col de l'utérus, un cancer de l'ovaire, une hyperplasie prostatique bénigne (HPB), une endométriose, des fibromes utérins, des myomes utérins, une hyperplasie endométriale, une dysménorrhée, des saignements dysfonctionnels de l'utérus (ménorragie, métrorragie), une puberté précoce, un hirsutisme, le syndrome des ovaires polykystiques, des maladies tumorales à dépendance hormonale, des infections à VIH ou le SIDA, des troubles neurologiques ou neurodégénératifs, le syndrome apparenté au SIDA, un sarcome de Kaposi, des tumeurs issues du cerveau et/ou du système nerveux et/ou des méninges, une démence, la maladie d'Alzheimer, des nausées et des vomissements, une douleur, des inflammations, des états pathologiques rhumatismaux et arthritiques.