公开(公告)号：US08633163B2

公开(公告)日：2014-01-21

申请号：US12524862

申请日：2007-01-29

申请人： Daniel Obrecht ,  Frank Gombert ,  Steve J. Demarco ,  Christian Ludin ,  Alexander Lederer ,  Christian Bisang ,  Odile Sellier-Kessler ,  Francoise Jung ,  Reshmi Mukherjee ,  Heiko Henze ,  Barbara Romagnoli

发明人： Daniel Obrecht ,  Frank Gombert ,  Steve J. Demarco ,  Christian Ludin ,  Alexander Lederer ,  Christian Bisang ,  Odile Sellier-Kessler ,  Francoise Jung ,  Reshmi Mukherjee ,  Heiko Henze ,  Barbara Romagnoli

IPC分类号： A61K38/00 ,  C07K14/72 ,  C07K14/705 ,  A61K38/04 ,  C07K5/00 ,  C07K7/00 ,  C07K16/00 ,  C07K17/00

CPC分类号： C07K7/64 ,  A61K38/00 ,  C07K5/02 ,  C07K5/101 ,  C07K5/1013 ,  C07K5/1016 ,  C07K5/1021 ,  C07K5/1024 ,  C07K7/06 ,  C07K7/08

摘要： Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed chain of 4 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to agonize or to antagonize GPCR receptors such as CXCR3, urotensin and CCR10. They can be used as medicaments to treat or prevent diseases such as cardiovascular disorders, dermatological disorders, endocrine system and hormone disorders, metabolic diseases, inflammatory diseases, neurological diseases, respiratory diseases, haematological diseases and cancer. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

摘要翻译： 通式（I）的模板固定的β-发夹肽模拟物，其中Z是4个α-氨基酸残基的模板固定链，其取决于其在链中的位置（从N-末端氨基酸开始计数）为 Gly或某些类型，其作为上述式中的其余符号在说明书和权利要求及其盐中定义，具有激动或拮抗GPCR受体如CXCR3，尿素调节素和CCR10的性质。 它们可以用作治疗或预防心血管疾病，皮肤病，内分泌系统和激素失调，代谢疾病，炎性疾病，神经疾病，呼吸系统疾病，血液病和癌症等疾病的药物。 这些β-发夹肽模拟物可以通过基于混合固相和溶液相合成策略的方法制备。

公开(公告)号：US20120283168A1

公开(公告)日：2012-11-08

申请号：US13510864

申请日：2010-11-18

申请人： Francoise Jung ,  Frank Otto Gombert ,  Daniel Obrecht ,  Christian Bisang ,  Sophie Barthélémy ,  Alexander Lederer ,  Eric Chevalier

发明人： Francoise Jung ,  Frank Otto Gombert ,  Daniel Obrecht ,  Christian Bisang ,  Sophie Barthélémy ,  Alexander Lederer ,  Eric Chevalier

IPC分类号： A61K38/12 ,  A61P3/00 ,  A61P29/00 ,  A61P25/00 ,  A61P11/00 ,  C07K1/12 ,  A61P27/02 ,  A61P35/00 ,  A61P7/00 ,  A61P11/06 ,  A61P37/06 ,  C07K7/64 ,  A61P1/00

CPC分类号： A61K38/00 ,  C07K7/06 ,  C07K7/08 ,  C07K7/64

摘要： Novel template-fixed β-hairpin peptidomimetics of the general formula (I) wherein the single elements T or P are α-amino acid residues connected in either direction which, depending on their positions in the chain, are as defined in the description and the claims, and salts thereof, have the property to antagonize the receptor CCR10. They can be used as medicaments to treat or prevent diseases or conditions in the area of dermatological and cutaneous disorders, inflammation, allergic disorders, respiratory diseases, diseases of the gastro-intestinal tract, ophthalmic diseases, haematology and cancer. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

摘要翻译： 通式（I）的新型模板固定型和平滑型肽模拟物，其中单元素T或P是沿任一方向连接的α-氨基酸残基，其取决于其在链中的位置如说明书中所定义， 权利要求书及其盐具有拮抗受体CCR10的性质。 它们可以用作治疗或预防皮肤病和皮肤疾病，炎症，过敏性疾病，呼吸系统疾病，胃肠道疾病，眼科疾病，血液学和癌症领域的疾病或病症的药物。 这些可以通过基于混合固相和溶液相合成策略的方法制造。

公开(公告)号：US20100093644A1

公开(公告)日：2010-04-15

申请号：US12524862

申请日：2007-01-29

申请人： Daniel Obrecht ,  Frank Gombert ,  Steve J. Demarco ,  Christian Ludin ,  Alexander Lederer ,  Christian Bisang ,  Odile Sellier-Kessler ,  Francoise Jung ,  Reshmi Mukherjee ,  Heiko Henze ,  Barbara Romagnoli

发明人： Daniel Obrecht ,  Frank Gombert ,  Steve J. Demarco ,  Christian Ludin ,  Alexander Lederer ,  Christian Bisang ,  Odile Sellier-Kessler ,  Francoise Jung ,  Reshmi Mukherjee ,  Heiko Henze ,  Barbara Romagnoli

IPC分类号： A61K38/07 ,  C07K5/10

CPC分类号： C07K7/64 ,  A61K38/00 ,  C07K5/02 ,  C07K5/101 ,  C07K5/1013 ,  C07K5/1016 ,  C07K5/1021 ,  C07K5/1024 ,  C07K7/06 ,  C07K7/08

摘要： Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed chain of 4 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to agonize or to antagonize GPCR receptors such as CXCR3, urotensin and CCR10. They can be used as medicaments to treat or prevent diseases such as cardiovascular disorders, dermatological disorders, endocrine system and hormone disorders, metabolic diseases, inflammatory diseases, neurological diseases, respiratory diseases, haematological diseases and cancer. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

摘要翻译： 通式（I）的模板固定和半乳糖肽模拟物，其中Z是4个α-氨基酸残基的模板固定链，其取决于其在链中的位置（从N-末端氨基酸开始计数） 是Gly，或某些类型，其作为上述式中的其余符号在说明书和权利要求书及其盐中定义，具有激动或拮抗GPCR受体如CXCR3，尿素调节素和CCR10的性质。 它们可以用作治疗或预防心血管疾病，皮肤病，内分泌系统和激素失调，代谢疾病，炎性疾病，神经疾病，呼吸系统疾病，血液病和癌症等疾病的药物。 这些可以通过基于混合固相和溶液相合成策略的方法制造。

公开(公告)号：US20090118134A1

公开(公告)日：2009-05-07

申请号：US10579104

申请日：2003-11-15

申请人： Jan Wim Vrijbloed ,  Daniel Obrecht ,  Sergio Locurio ,  Frank Otto Gombert ,  Christian Ludin ,  Francoise Jung

发明人： Jan Wim Vrijbloed ,  Daniel Obrecht ,  Sergio Locurio ,  Frank Otto Gombert ,  Christian Ludin ,  Francoise Jung

IPC分类号： C40B30/04 ,  C07K7/00 ,  C40B40/10 ,  C40B40/02

CPC分类号： C07K1/047 ,  C12N15/1037 ,  C40B40/02

摘要： Template-fixed β-hairpin mime tics of the general formula R1-Cys-Z-Cys-R2 (1) wherein the two Cys residues are bridged by a disulfide bond thereby forming a cyclic peptide; R1 and R2 are preferably Glu-Thr and Thr-Lys; or Lys-Thr and Thr-Glu; or Thr-Glu and Lys-Thr, or Thr-Lys and Glu-Thr; or Leu-Glu and Lys-Val; or Val-Lys and Glu-Leu; or Glu-Leu and Val-Lys; or Lys-Leu and Val-Glu; or Asn-Gly and Lys-Val; or Val-Gly and Lys-Asn; or Gly-Asn and Val-Lys; or Gly-Val and Asn-Lys; or Gly-Gly and Gly-Gly; or Glu-Leu-Lys and Glu-Val-Lys; or Lys-Val-Glu and Lys-Leu-Glu; or Leu-Glu-Lys and Glu-Lys-Val; or Val-Lys-Glu and Lys-Glu-Leu; or Glu-Lys-Leu and Val-Glu-Lys; or Lys-Glu-Val and Leu-Lys-Glu; or Lys-Glu-Leu and Val-Lys-Glu; or Glu-Lys-Val and Leu-Glu-Lys; or Lys-Val-Gly and Gly-Leu-Glu; or Glu-Leu-Gly and Gly-Val-Lys; or Val-Lys-Gly and Gly-Glu-Leu; or Leu-Glu-Gly and Gly-Lys-Val; or Val-Gly-Lys and Glu-Gly-Leu; or Leu-Gly-Glu and Lys-Gly-Val; or Gly-Gly-Gly and Gly-Gly-Gly; and Z is a chain of n amino acid residues with n being an integer form 4 to 20 and with each of these n amino acid residues being, independently, derived from any naturally occurring L-α-amino acid are provided. Libraries comprising a plurality of these templates can be used for the construction of phage display derived template-fixed β-hairpin mimetics generating phage display libraries with very high binding constants to targets, thus combining the advantage of screening of large phage display derived template-fixed β-hairpin libraries which in turn considerably facilitates structure-activity studies, and hence the discovery of new molecules with potent activities and with novel selectivities towards different types of targets.

摘要翻译： 通式R1-Cys-Z-Cys-R2（1）的模板固定β-发夹制剂，其中两个Cys残基用二硫键桥接，从而形成环肽; R1和R2优选为Glu-Thr和Thr-Lys; 或Lys-Thr和Thr-Glu; 或Thr-Glu和Lys-Thr，或Thr-Lys和Glu-Thr; 或Leu-Glu和Lys-Val; 或Val-Lys和Glu-Leu; 或Glu-Leu和Val-Lys; 或Lys-Leu和Val-Glu; 或Asn-Gly和Lys-Val; 或Val-Gly和Lys-Asn; 或Gly-Asn和Val-Lys; 或Gly-Val和Asn-Lys; 或Gly-Gly和Gly-Gly; 或Glu-Leu-Lys和Glu-Val-Lys; 或Lys-Val-Glu和Lys-Leu-Glu; 或Leu-Glu-Lys和Glu-Lys-Val; 或Val-Lys-Glu和Lys-Glu-Leu; 或Glu-Lys-Leu和Val-Glu-Lys; 或Lys-Glu-Val和Leu-Lys-Glu; 或Lys-Glu-Leu和Val-Lys-Glu; 或Glu-Lys-Val和Leu-Glu-Lys; 或Lys-Val-Gly和Gly-Leu-Glu; 或Glu-Leu-Gly和Gly-Val-Lys; 或Val-Lys-Gly和Gly-Glu-Leu; 或Leu-Glu-Gly和Gly-Lys-Val; 或Val-Gly-Lys和Glu-Gly-Leu; 或Leu-Gly-Glu和Lys-Gly-Val; 或Gly-Gly-Gly和Gly-Gly-Gly; 并且Z是n个氨基酸残基的链，n是4至20的整数，并且这些n个氨基酸残基中的每一个独立地衍生自任何天然存在的L-α-氨基酸。 包含多个这些模板的文库可用于构建噬菌体展示衍生的模板固定的β-发夹模拟物，其产生具有非常高的结合常数的靶标的噬菌体展示文库，因此结合筛选大噬菌体展示衍生模板固定的优点 β-发夹文库反过来极大地促进结构活性研究，从而发现具有有效活性和对不同类型靶标具有新选择性的新分子。

公开(公告)号：US20090054345A1

公开(公告)日：2009-02-26

申请号：US11816589

申请日：2005-02-17

申请人： Steven J. DeMarco ,  Kerstin Moehle ,  Heiko Henze ,  Odile Sellier ,  Francoise Jung ,  Frank Gombert ,  Daniel Obrecht ,  Christian Ludin

发明人： Steven J. DeMarco ,  Kerstin Moehle ,  Heiko Henze ,  Odile Sellier ,  Francoise Jung ,  Frank Gombert ,  Daniel Obrecht ,  Christian Ludin

IPC分类号： A61K38/08 ,  C07K7/06 ,  A61P31/00 ,  A61P35/00 ,  A61P37/00 ,  A61P29/00

CPC分类号： C07K7/06 ,  A61K38/00 ,  C07K1/061 ,  C07K7/08 ,  C07K7/64

摘要： Templates-fixed β-hairpin peptidomimetics of the general formulae (I), wherein Z is a chain of 11α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or Pro(4NHCOPhe), or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to inhibit proteases, in particular serine proteases, especially Cathepsin G or Elastase or Tryptase. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.

摘要翻译： 模板固定的通式（I）的β-发夹肽模拟物，其中Z是11α-氨基酸残基的链，其取决于其在链中的位置（从N-末端氨基酸开始计数）为Gly，或 Pro或Pro（4NHCOPhe）或某些类型，其作为上述式中的其余符号在说明书和权利要求书及其盐中定义，具有抑制蛋白酶，特别是丝氨酸蛋白酶，特别是组织蛋白酶的性质 G或Elastase或Tryptase。 这些β-发夹肽模拟物可以通过基于混合固相和溶液相合成策略的方法制备。