1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-4-phenylpiperidin-4-ol | 1221821-80-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-4-phenylpiperidin-4-ol
• 英文别名: 1-{[(3S,4R)-1-tert-Butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]-carbonyl}-4-phenylpiperidin-4-ol；[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]-(4-hydroxy-4-phenylpiperidin-1-yl)methanone
• CAS: 1221821-80-2
• 化学式: C₂₆H₃₂F₂N₂O₂
• 分子量: 442.549
• InChiKey: MHIILDKFLFPQES-FCHUYYIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  43.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (3S,4R)-1-叔丁基-4-(2,4-二氟苯基)吡咯烷-3-羧酸 、 4-苯基-4-羟基哌啶 在 1-丙基磷酸酐 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 以68%的产率得到1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-4-phenylpiperidin-4-ol
  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

• 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.