公开(公告)号：US09878999B2

公开(公告)日：2018-01-30

申请号：US14035453

申请日：2013-09-24

申请人： H. Lee Moffitt Cancer Center and Research Institute, Inc.

发明人： Harshani R. Lawrence ,  Said M. Sebti ,  Sevil Ozcan

IPC分类号： A61K31/497 ,  C07D413/04 ,  C07D271/04 ,  C07D271/06

CPC分类号： C07D413/04 ,  C07D271/04 ,  C07D271/06

摘要： Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

公开(公告)号：US20180215742A1

公开(公告)日：2018-08-02

申请号：US15882094

申请日：2018-01-29

申请人： H. Lee Moffitt Cancer Center and Research Institute, Inc.

发明人： Harshani R. Lawrence ,  Said M. Sebti ,  Sevil Ozcan

IPC分类号： C07D413/04 ,  C07D271/04 ,  C07D271/06

CPC分类号： C07D413/04 ,  C07D271/04 ,  C07D271/06

摘要： Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

公开(公告)号：US10662180B2

公开(公告)日：2020-05-26

申请号：US15882094

申请日：2018-01-29

申请人： H. Lee Moffitt Cancer Center and Research Institute, Inc.

发明人： Harshani R. Lawrence ,  Said M. Sebti ,  Sevil Ozcan

IPC分类号： C07D271/06 ,  C07D417/00 ,  C07D413/00 ,  C07D401/04 ,  A61K31/41 ,  C07D413/04 ,  C07D271/04

摘要： Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

公开(公告)号：US20140073650A1

公开(公告)日：2014-03-13

申请号：US14035453

申请日：2013-09-24

申请人： H. Lee Moffitt Cancer Center and Research Institute, Inc

发明人： Harshani R. Lawrence ,  Said M. Sebti ,  Sevil Ozcan

IPC分类号： C07D413/04 ,  C07D271/06

CPC分类号： C07D413/04 ,  C07D271/04 ,  C07D271/06

摘要： Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

摘要翻译： 在二恶唑 - 异丙酰胺核心蛋白酶体抑制剂上集中文库合成和药物化学提供强烈抑制CT-L活性的铅化合物。 结构活性关系研究表明酰胺部分和两个苯环对合成改性敏感。 在A环中只有对位取代对于维持有效的CT-L抑制活性是重要的。 A环的对位疏水残基和B-环上的间位吡啶基显着改善了抑制作用。 间 - 吡啶基部分改善细胞渗透性。 A环的对位脂肪链的长度是关键的丙基产生最有效的抑制剂，而较短的（即乙基，甲基或氢）或更长（即丁基，丙基和己基）链显示逐渐降低的效力 。 引入邻位于醚部分的立体中心（即用甲基取代一个氢）在蛋白酶体CT-L活性抑制（S-对映异构体比R-对映异构体更有效35-40倍）中证明手性鉴别。