1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] | 1024604-71-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine]
• 英文别名: 1'-[6-[5-(Pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl]-5-(trifluoromethyl)spiro[3,4-dihydrochromene-2,4'-piperidine]
• CAS: 1024604-71-4
• 化学式: C₂₆H₂₃F₃N₆O₂
• 分子量: 508.503
• InChiKey: LFQBDZIKMOOKIP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  90.1
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  3-chloro-6-(5-pyridin-3-ylmethyl-[1,3,4]oxadiazol-2-yl)pyridazine 、 5-trifluoromethyl-3,4-dihydro-1'H-spiro(chromene-2,4'-piperidine)-1'-carboxylate hydrochloride 在 三乙胺 作用下， 以 正丁醇 为溶剂， 反应 48.0h， 以68%的产率得到1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine]
  参考文献：
  名称：

  Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs

  摘要：

  In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID(50) = 0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC(50) (mouse)= 2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg). (C) 2010 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2010.07.044

文献信息

• Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine]
  作者：Yoshikazu Uto、Yohei Kiyotsuka、Yuko Ueno、Yuriko Miyazawa、Hitoshi Kurata、Tsuneaki Ogata、Tsuneo Deguchi、Makiko Yamada、Nobuaki Watanabe、Masahiro Konishi、Nobuya Kurikawa、Toshiyuki Takagi、Satoko Wakimoto、Keita Kono、Jun Ohsumi

  DOI：10.1016/j.bmcl.2009.11.043

  日期：2010.1

  Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3 mg/kg) in our preliminary analysis. (C) 2009 Elsevier Ltd. All rights reserved.
• NICOTINYL RIBOSIDE COMPOUNDS AND THEIR USES
  申请人：Mitopower LLC

  公开号：EP3897666A2

  公开（公告）日：2021-10-27
• GLP-1R and GCGR Agonists, Formulations, and Methods of Use
  申请人：Spitfire Pharma LLC

  公开号：US20210290732A1

  公开（公告）日：2021-09-23

  This disclosure relates to the field of GLP-1R and GCGR agonists, formulations, and methods of using the same, including but not limited to dual agonist peptides of any of SEQ ID NOS. 1-10 or 12-27 conjugated to a non-ionic glycolipid surfactant.
• [EN] NICOTINYL RIBOSIDE COMPOUNDS AND THEIR USES<br/>[FR] COMPOSÉS NICOTINYL RIBOSIDE ET LEURS UTILISATIONS
  申请人：MITOPOWER LLC

  公开号：WO2020131578A2

  公开（公告）日：2020-06-25

  The disclosure provides nicotinamide riboside (NR), the reduced form of NR (NRH), nicotinic acid riboside (NAR), the reduced form of NAR (NARH), derivatives thereof, compositions thereof and uses thereof. The NR and NAR derivatives have improved stability and bioavailability compared to NR and NAR. NR, NRH, NAR, NARH, and derivatives thereof can increase intracellular NAD+ levels, and can enhance mitochondrial and cellular function and cell viability. Therefore, NR, NRH, NAR, NARH, and derivatives thereof, whether alone or in combination with one or more additional therapeutic agents (e.g., a PARP inhibitor), are useful for treating mitochondrial diseases, mitochondria-related diseases and conditions, and other disorders and conditions.
• Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs
  作者：Yoshikazu Uto、Yuko Ueno、Yohei Kiyotsuka、Yuriko Miyazawa、Hitoshi Kurata、Tsuneaki Ogata、Makiko Yamada、Tsuneo Deguchi、Masahiro Konishi、Toshiyuki Takagi、Satoko Wakimoto、Jun Ohsumi

  DOI：10.1016/j.ejmech.2010.07.044

  日期：2010.11

  In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1'-6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID(50) = 0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC(50) (mouse)= 2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg). (C) 2010 Elsevier Masson SAS. All rights reserved.