N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘基)-1H-吡唑-1-基]乙基]苯甲酰]-beta-丙氨酸 | 870823-12-4

• 物质功能分类: 生物化工 - 氨基酸及其衍生物 - 丙氨酸类衍生物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘基)-1H-吡唑-1-基]乙基]苯甲酰]-beta-丙氨酸
• 中文别名: N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘基)-1H-吡唑-1-基]乙基]苯甲酰]-BETA-丙氨酸；N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘)-1H-吡唑]乙基]苯甲酰基]-β-丙氨酸
• 英文名称: MK-0893
• 英文别名: N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine；N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alanine；(S)-3-(4-(1-(3-(3,5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl)ethyl)benzamido)propanoic acid；3-[[4-[(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid
• CAS: 870823-12-4
• 化学式: C₃₂H₂₇Cl₂N₃O₄
• 分子量: 588.49
• InChiKey: DNTVJEMGHBIUMW-IBGZPJMESA-N

物化性质

• 沸点：
  814.0±65.0 °C(Predicted)
• 密度：
  1.33
• 溶解度：
  DMSO 中≥24.05 mg/mL；不溶于水； ≥4.8 mg/mL，乙醇溶液，温和加热和超声波

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  41
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  93.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-(3,5-二氯苯基)-3-氧代-丙酸乙酯 在 四(三苯基膦)钯 、 溶剂黄146 、 三乙胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙二醇二甲醚 、 二氯甲烷 为溶剂， 反应 9.17h， 生成 N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘基)-1H-吡唑-1-基]乙基]苯甲酰]-beta-丙氨酸
  参考文献：
  名称：

  Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes

  摘要：

  A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl) -5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)-carbonyl]-beta-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC50 of 6.6 nM) and functional cAMP activity (IC50 of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC50 values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

  DOI：

  10.1021/jm300579z

文献信息

• HETEROCYCLIC DERIVATIVES AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
  申请人：Isabel Elise

  公开号：US20110301143A1

  公开（公告）日：2011-12-08

  Heterocyclic compounds of structural formula (I), or a pharmaceutically acceptable salt thereof, wherein W is a R 1 — substituted heteroaryl, R 1 is an heteroaryl ring substituted with an ester or carboxylic acid containing radical, X-T is N—CR 5 R 6 , C═CR 5 or CR 13 —CR 5 R 6 , Y is a bond or —C(O)—, a and b represent an integer selected from 1 to 4, and Ar is an optionally substituted phenyl or naphtyl, are inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) The heterocyclic compounds are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, atherosclerosis, obesity, diabetes, neurological disease, Metabolic Syndrome, insulin resistance, cancer, liver steatosis, and non-alcoholic steatohepatitis.

  结构式（I）的杂环化合物，或其药学上可接受的盐，其中W是R1-取代的杂芳基，R1是取代有酯基或羧基的杂芳基环，X-T是N—CR5R6，C═CR5或CR13—CR5R6，Y是键或—C(O)—，a和b代表选自1到4的整数，Ar是可选择取代的苯基或萘基，是硬脂酰辅酶A 9-脱饱和酶（SCD）的抑制剂。这些杂环化合物对于预防和治疗与异常脂质合成和代谢有关的疾病非常有用，包括心血管疾病、动脉粥样硬化、肥胖症、糖尿病、神经系统疾病、代谢综合征、胰岛素抵抗、癌症、肝脂肪变性和非酒精性脂肪肝。
• [EN] SPIROXAZOLIDINONE COMPOUNDS<br/>[FR] COMPOSÉS SPIROXAZOLIDINONE
  申请人：MERCK SHARP & DOHME

  公开号：WO2012024183A1

  公开（公告）日：2012-02-23

  Substituted spirocyclic amines of structural formula (I) are selective antagonists of the somatostatin subtype receptor 5 (SSTR5) and are useful for the treatment, control or prevention of disorders responsive to antagonism of SSTR5, such as Type 2 diabetes, insulin resistance, lipid disorders, obesity, atherosclerosis, Metabolic Syndrome, depression, and anxiety.

  结构式（I）的螺环胺是生长抑素亚型受体5（SSTR5）的选择性拮抗剂，可用于治疗、控制或预防对SSTR5拮抗敏感的疾病，如2型糖尿病、胰岛素抵抗、脂质紊乱、肥胖、动脉粥样硬化、代谢综合征、抑郁症和焦虑症。
• AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
  申请人：Biftu Tesfaye

  公开号：US20100120863A1

  公开（公告）日：2010-05-13

  The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

  本发明涉及结构式I的新型取代氨基四氢吡喃衍生物，它们是二肽基肽酶-IV酶的抑制剂，可用于治疗或预防二肽基肽酶-IV酶参与的疾病，如糖尿病，特别是2型糖尿病。该发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在预防或治疗二肽基肽酶-IV酶参与的疾病中的用途。
• [EN] ANTIDIABETIC TRICYCLIC COMPOUNDS<br/>[FR] COMPOSÉS TRICYCLIQUES ANTIDIABÉTIQUES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015176267A1

  公开（公告）日：2015-11-26

  Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR 40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds may be useful in the treatment of Type 2 diabetes mellitus and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

  结构式（I）的新化合物及其药学上可接受的盐是G蛋白偶联受体40（GPR 40）的激动剂，可能在治疗、预防和抑制由G蛋白偶联受体40介导的疾病方面有用。这些化合物可能在治疗2型糖尿病以及通常与该疾病相关的疾病，包括肥胖和脂质紊乱，如混合型或糖尿病性脂质代谢异常、高脂血症、高胆固醇血症和高甘油三酯血症方面有用。
• Pyrazole derivatives, compositions containing such compounds and methods of use
  申请人：Parmee R. Emma

  公开号：US20050272794A1

  公开（公告）日：2005-12-08

  Pyrazoles having a naphthyl group attached are disclosed. The compounds are useful for treating type 2 diabetes and related conditions. Pharmaceutical compositions and methods of treatment are also included.

  揭示了附有萘基团的吡唑类化合物。这些化合物可用于治疗2型糖尿病及相关疾病。还包括药物组合物和治疗方法。