5-(1,8-naphthyridin-2-yl)pentanoic acid | 1314795-64-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 5-(1,8-naphthyridin-2-yl)pentanoic acid
• 英文别名: 5-(1,8-Naphthyridin-2-yl)pentanoicacid
• CAS: 1314795-64-6
• 化学式: C₁₃H₁₄N₂O₂
• 分子量: 230.266
• InChiKey: GFQHPFMSQSNNRV-UHFFFAOYSA-N

物化性质

• 沸点：
  434.6±35.0 °C(Predicted)
• 密度：
  1.231±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  63.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(1,8-naphthyridin-2-yl)pentanoic acid 在 N-甲基吗啉 、 palladium on activated charcoal 、 氢气 、 1-羟基苯并三唑 、 1-丙基磷酸酐 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 乙酸乙酯 、 乙腈 为溶剂， 反应 104.0h， 生成 ethyl 2-(1-(3-fluorobenzenesulfonyl)azetidine-3-carboxamido)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanamido)propanoate
  参考文献：
  名称：

  [EN] AZETIDINE DERIVATIVES FOR THE TREATMENT OF INTEGRIN ASSOCIATED DISEASES
  [FR] DÉRIVÉS D'AZÉTIDINE POUR LE TRAITEMENT DE MALADIES SE RAPPORTANT AUX INTÉGRINES

  摘要：

  该发明涉及公式（I）的新化合物，这些化合物能够作为avβ6整合素拮抗剂发挥作用，它们在治疗疾病中的用途，它们的制备方法以及包含这些化合物的用于此类目的组合物（I），其中R1从以下中选择：R1a，-C（O）R1a，-C（O）OR1a，-C（O）NHR1a，-C（O）N（R1a）2，-SO2R1a，其中R1a各自独立选择自：烷基，烯烃基，炔烃基，芳基，杂芳基，烷基芳基或烷基杂芳基，每种均可选择性取代；R2从以下中选择：氢，卤素，可选择性取代的烷基或可选择性取代的烷氧基；R2a各自独立选择自：氢，卤素，可选择性取代的烷基或可选择性取代的烷氧基；R3从以下中选择：氢，可选择性取代的烷基或可选择性取代的烷氧基；R4为羟基；Ar1为可选择性取代的杂芳基或双环杂芳基；L为连接物；或其药用可接受盐。

  公开号：

  WO2022008918A1
• 作为产物：
  描述：

  2-氨基-3-吡啶甲醛 在 lithium hydroxide monohydrate 、 水 、 L-脯氨酸 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 36.0h， 生成 5-(1,8-naphthyridin-2-yl)pentanoic acid
  参考文献：
  名称：

  Discovery of a potent and selective small molecule hGPR91 antagonist

  摘要：

  GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 mu M)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; > 100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; > 100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.04.091

文献信息

• Structure Activity Relationships of α_v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents
  作者：James Adams、Edward C. Anderson、Emma E. Blackham、Yin Wa Ryan Chiu、Thomas Clarke、Natasha Eccles、Luke A. Gill、Joshua J. Haye、Harvey T. Haywood、Christian R. Hoenig、Marius Kausas、Joelle Le、Hannah L. Russell、Christopher Smedley、William J. Tipping、Tom Tongue、Charlotte C. Wood、Jason Yeung、James E. Rowedder、M. Jonathan Fray、Thomas McInally、Simon J. F. Macdonald

  DOI：10.1021/ml5002079

  日期：2014.11.13

  Antagonism of alpha(v)beta(6) is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an alpha(v)beta(3) antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved alpha(v)beta(6) activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan av antagonists having ca. 100 nM potency against alpha(v)beta(3), alpha(v)beta(5), alpha(v)beta(6), and av beta 8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC(50) values between the integrins in question) for alpha(v)beta(3) and alpha(v)beta(5).
• [EN] AZETIDINE DERIVATIVES FOR THE TREATMENT OF INTEGRIN ASSOCIATED DISEASES<br/>[FR] DÉRIVÉS D'AZÉTIDINE POUR LE TRAITEMENT DE MALADIES SE RAPPORTANT AUX INTÉGRINES
  申请人：UNIV NOTTINGHAM

  公开号：WO2022008918A1

  公开（公告）日：2022-01-13

  The invention relates to novel compounds of formula (I), the compounds being capable of acting as avβ6 integrin antagonists, their use in the treatment of disease, their methods of manufacture and compositions comprising said compounds for such purposes (I) wherein R1 is selected from: R1a, -C(O)R1a, -C(O)OR1a -C(O)NHR1a, -C(O)N(R1a)2, -SO2R1a, wherein R1a are each independently selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which may be optionally substituted; R2 is selected from: hydrogen, halogen, optionally substituted alkyl or optionally substituted alkoxyl; R2a are each independently selected from: hydrogen, halogen, optionally substituted alkyl or optionally substituted alkoxyl; R3 is selected from: hydrogen, optionally substituted alkyl or optionally substituted alkoxyl; R4 is hydroxyl; Ar1 is an optionally substituted heteroaryl or bicyclic heteroaryl; and L is a linker; or a pharmaceutically acceptable salt thereof.

  该发明涉及公式（I）的新化合物，这些化合物能够作为avβ6整合素拮抗剂发挥作用，它们在治疗疾病中的用途，它们的制备方法以及包含这些化合物的用于此类目的组合物（I），其中R1从以下中选择：R1a，-C（O）R1a，-C（O）OR1a，-C（O）NHR1a，-C（O）N（R1a）2，-SO2R1a，其中R1a各自独立选择自：烷基，烯烃基，炔烃基，芳基，杂芳基，烷基芳基或烷基杂芳基，每种均可选择性取代；R2从以下中选择：氢，卤素，可选择性取代的烷基或可选择性取代的烷氧基；R2a各自独立选择自：氢，卤素，可选择性取代的烷基或可选择性取代的烷氧基；R3从以下中选择：氢，可选择性取代的烷基或可选择性取代的烷氧基；R4为羟基；Ar1为可选择性取代的杂芳基或双环杂芳基；L为连接物；或其药用可接受盐。
• Discovery of a potent and selective small molecule hGPR91 antagonist
  作者：Debnath Bhuniya、Dhananjay Umrani、Bhavesh Dave、Deepak Salunke、Gagan Kukreja、Jayasagar Gundu、Minakshi Naykodi、Nadim S. Shaikh、Prasad Shitole、Santosh Kurhade、Siddhartha De、Sreemita Majumdar、Srinivasa B. Reddy、Suhas Tambe、Yogesh Shejul、Anita Chugh、Venkata P. Palle、Kasim A. Mookhtiar、Doris Cully、Joseph Vacca、Prasun K. Chakravarty、Ravi P. Nargund、Samuel D. Wright、Michael P. Graziano、Sheo B. Singh、Sophie Roy、Tian-Quan Cai

  DOI：10.1016/j.bmcl.2011.04.091

  日期：2011.6

  GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 mu M)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; > 100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; > 100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay. (C) 2011 Elsevier Ltd. All rights reserved.