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    Cysteine protease inhibitors effective for in vivo use
    4.
    发明授权
    Cysteine protease inhibitors effective for in vivo use 失效
    半胱氨酸蛋白酶抑制剂有效用于体内使用

    公开(公告)号：US5374623A

    公开(公告)日：1994-12-20

    申请号：US932791

    申请日：1992-08-20

    申请人： Mary P. Zimmerman ,  Eugene R. Bissell ,  Robert E. Smith

    发明人： Mary P. Zimmerman ,  Eugene R. Bissell ,  Robert E. Smith

    IPC分类号： A61K38/55 ,  A61P1/02 ,  A61P29/00 ,  A61P33/02 ,  A61P43/00 ,  C07C237/22 ,  C07C271/18 ,  C07C271/22 ,  C07C279/14 ,  C07D295/215 ,  C07K5/065 ,  A61K37/02 ,  C07K5/06 ,  C07K5/08 ,  C07K5/10

    CPC分类号： C07D295/215 ,  C07C271/18 ,  C07C271/22 ,  C07C279/14

    摘要： A method of treating medical conditions with proteinase inhibitors of the formula: ##STR1## wherein B is H or an amino acid blocking group for the N-terminal amino acid nitrogen;R.sub.1 is an optionally protected .alpha.-amino acid side chain such that P.sub.2 is the residue of an .alpha.-amino acid selected from the group consisting of phenylalanine (Phe), leucine (Leu), tyrosine (Tyr) and valine (Val), and substituted analogs thereof, particularly including Tyr(OMe);R.sub.2 is an optionally protected .alpha.-amino acid side chain such that P.sub.1 is the residue of an .alpha.-amino acid selected from the group consisting of alanine (Ala), arginine (Arg), aspartic acid (Asp), glutamic acid (Glu), histidine (His), homophenylalanine (HPhe), phenylalanine (Phe), ornithine (Orn), serine (Ser) and threonine (Thr), and substituted analogs thereof;X is a fluorine-free leaving group selected from the group consisting of phenoxy, substituted phenoxy and heterophenoxy;E and G are one or more atoms more electronegative than carbon; andD is hydrogen, methyl or a substituted methyl.

    摘要翻译： 用下式的蛋白酶抑制剂治疗医学病症的方法：其中B是H或N-末端氨基酸氮的氨基酸封闭基团; R1是任选保护的α-氨基酸侧链，使得P2是选自苯丙氨酸（Phe），亮氨酸（Leu），酪氨酸（Tyr）和缬氨酸（Val）的α-氨基酸的残基，以及 其取代的类似物，特别包括Tyr（OMe）; R2是任选保护的α-氨基酸侧链，使得P1是选自丙氨酸（Ala），精氨酸（Arg），天冬氨酸（Asp），谷氨酸（Glu）的α-氨基酸的残基。 ，组氨酸（His），高苯丙氨酸（HPhe），苯丙氨酸（Phe），鸟氨酸（Orn），丝氨酸（Ser）和苏氨酸（Thr）及其取代的类似物; X是选自苯氧基，取代的苯氧基和异苯氧基的无氟离去基团; E和G是一个或多个比碳更负电的原子; D为氢，甲基或取代甲基。

    Cysteine protease inhibitors containing heterocyclic leaving groups
    5.
    发明授权
    Cysteine protease inhibitors containing heterocyclic leaving groups 失效
    含有杂环离去基团的半胱氨酸蛋白酶抑制剂

    公开(公告)号：US06297277B1

    公开(公告)日：2001-10-02

    申请号：US09357253

    申请日：1999-07-20

    申请人： Mary P. Zimmerman ,  Robert E. Smith

    发明人： Mary P. Zimmerman ,  Robert E. Smith

    IPC分类号： A01N3712

    CPC分类号： C07D213/64 ,  A61K31/34 ,  A61K31/35 ,  A61K31/40 ,  A61K31/44 ,  A61K31/443 ,  A61K31/505 ,  A61K31/5375 ,  A61K47/62 ,  C07D207/16 ,  C07D213/80 ,  C07D239/34 ,  C07D295/215 ,  C07D307/58 ,  C07D307/60 ,  C07D307/62 ,  C07D309/38 ,  C07D405/12 ,  Y02A50/411 ,  Y02A50/414 ,  Y02A50/423

    摘要： A class of cysteine protease inhibitors which inactivate a cysteine protease by covalently bonding to the protease and releasing a heterocyclic leaving group is presented. The cysteine protease inhibitors of the present invention comprise a first portion which targets a desired cysteine protease and positions the inhibitor near the thiolate anion portion of the active site of the protease, and a second portion which covalently bonds to the cysteine protease and irreversibly deactivates that protease by providing a carbonyl or carbonyl-equivalent which is attacked by the thiolate anion of the active site of the cysteine protease to sequentially cleave a heterocyclic leaving group. The heterocyclic leaving group of the protease inhibitor is of the formula: —O—Het, where Het is a heterocycle having 4-7 atoms in the ring, with at least one of the heterocycle atoms being N, O or S.

    摘要翻译： 提出了一类半胱氨酸蛋白酶抑制剂，其通过共价键合蛋白酶和释放杂环离去基团而使半胱氨酸蛋白酶失活。 本发明的半胱氨酸蛋白酶抑制剂包含第一部分，其靶向所需的半胱氨酸蛋白酶，并将抑制剂置于蛋白酶活性位点的硫醇盐阴离子部分附近，第二部分与半胱氨酸蛋白酶共价结合，并且不可逆地使 通过提供被半胱氨酸蛋白酶的活性位点的硫醇盐阴离子攻击的羰基或羰基等价物来顺序地切割杂环离去基团。 蛋白酶抑制剂的杂环离去基团具有下式：-O-Het，其中Het是在环中具有4-7个原子的杂环，其中至少一个杂环原子是N，O或S.