(3S,4R)-4-(2,4-difluorophenyl)-1-pyridazin-3-ylpyrrolidine-3-carboxylic acid hydrochloride | 923948-68-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (3S,4R)-4-(2,4-difluorophenyl)-1-pyridazin-3-ylpyrrolidine-3-carboxylic acid hydrochloride
• 英文别名: (3S,4R)-4-(2,4-difluorophenyl)-1-pyridazin-3-ylpyrrolidine-3-carboxylic acid;hydrochloride
• CAS: 923948-68-9
• 化学式: C₁₅H₁₃F₂N₃O₂*ClH
• 分子量: 341.745
• InChiKey: STPIGSGOLUEHPE-ZVWHLABXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.48
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  66.3
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3R,4s,5S)-3,5-dimethyl-4-propylpiperidin-4-ol 、 (3S,4R)-4-(2,4-difluorophenyl)-1-pyridazin-3-ylpyrrolidine-3-carboxylic acid hydrochloride 在 1-丙基磷酸酐 、 三乙胺 、 盐酸 作用下， 以 二氯甲烷 、 乙酸乙酯 、 乙醚 为溶剂， 反应 72.0h， 生成 (3R,4R,5S)-1-{[(3S,4R)-4-(2,4-difluorophenyl)-1-pyridazin-3-ylpyrrolidin-3-yl]carbonyl}-3,5-dimethyl-4-propylpiperidin-4-ol hydrochloride
  参考文献：
  名称：

  Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans

  摘要：

  The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

  DOI：

  10.1021/jm9017866
• 作为产物：
  描述：

  methyl (3S,4R)-4-(2,4-difluorophenyl)-1-pyridazin-3-ylpyrrolidin-3-yl-carboxylate 在 水 、 lithium hydroxide 、 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 5.0h， 以97%的产率得到(3S,4R)-4-(2,4-difluorophenyl)-1-pyridazin-3-ylpyrrolidine-3-carboxylic acid hydrochloride
  参考文献：
  名称：

  Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans

  摘要：

  The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

  DOI：

  10.1021/jm9017866

文献信息

• Use of Mc4 Receptor Agonist Compounds
  申请人：McMurray Gordon

  公开号：US20080234280A1

  公开（公告）日：2008-09-25

  This invention relates to the use of an MC4 receptor agonist compound for the manufacture of a medicament for the treatment of lower urinary tract dysfunction.

  该发明涉及使用MC4受体激动剂化合物制造治疗下尿路功能障碍的药物。
• Piperidinoyl-Pyrrolidine and Piperidinoyl-Piperidine Compounds
  申请人：Andrews Mark David

  公开号：US20080269233A1

  公开（公告）日：2008-10-30

  The present invention relates to a class of compounds of general formula (I) and the salts, hydrates, solvates, polymorphs and prodrugs wherein n, R 6 , R 7 and R 10 are as defined herein and especially to MCR4 agonist compounds of formula (I), to their use in medicine, particularly in the treatment of sexual dysfunction and obesity, to intermediates useful in their synthesis and to compositions containing them.

  本发明涉及一类通式（I）的化合物及其盐、水合物、溶剂物、多晶形和前药，其中n、R6、R7和R10如本文所定义，特别是MCR4激动剂化合物的通式（I），它们在医学上的应用，特别是在治疗性功能障碍和肥胖症方面的应用，以及有用于它们合成的中间体和含有它们的组合物。
• WO2007/15162
  申请人：——

  公开号：——

  公开（公告）日：——
• Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans
  作者：Mark I. Lansdell、David Hepworth、Andrew Calabrese、Alan D. Brown、Julian Blagg、Denise J. Burring、Peter Wilson、David Fradet、T. Bruce Brown、Faye Quinton、Neela Mistry、Kim Tang、Natalie Mount、Peter Stacey、Nick Edmunds、Cathryn Adams、Samantha Gaboardi、Stevie Neal-Morgan、Chris Wayman、Susan Cole、Joanne Phipps、Mark Lewis、Hugh Verrier、Val Gillon、Neil Feeder、Anne Heatherington、Stefan Sultana、Scott Haughie、Steven W. Martin、Maria Sudworth、Sarah Tweedy

  DOI：10.1021/jm9017866

  日期：2010.4.22

  The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.