β-hairpin peptidomimetics

Inventors

Gombert, Frank Otto • Obrecht, Daniel • Lederer, Alexander • Zimmermann, Johann • Oefner, Christian

Assignees

Spexis AG

Abstract

β-Hairpin peptidomimetics of the general formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-DPro7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Xaa13-Xaa14-Xaa15-Pro16-), disulfide bond between Cys4 and Cys11, and pharmaceutically acceptable salts thereof, with Xaa3, Xaa6, Xaa8, Xaa13, Xaa14 and Xaa15 being amino acid residues of certain types which are defined in the description and the claims, have favorable pharmacological properties and can be used for preventing HIV infections in healthy individuals or for slowing and halting viral progression in infected patients; or where cancer is mediated or resulting from CXCR4 receptor activity; or where immunological diseases are mediated or resulting from CXCR4 receptor activity; or for treating immunosuppression; or during apheresis collections of peripheral blood stem cells and/or as agents to induce mobilization of stem cells to regulate tissue repair.These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

Core Innovation

The invention relates to β-hairpin cyclized peptidomimetics of the general formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-DPro7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Xaa13-Xaa14-Xaa15-Pro16-), comprising a disulfide bond between Cys4 and Cys11, and pharmaceutically acceptable salts thereof. The residue constraints include Xaa3 being Tyr; Tyr(Me); or Tyr(CF3), Xaa6 being Ala; or Acc, Xaa8 being Orn(iPr), Xaa13 being Gln; or Glu, Xaa14 being Lys(iPr), and Xaa15 being DPro; or D-Lys(iPr), with a proviso linking Xaa6 and Xaa15.

The compounds are described as providing CXCR4 antagonizing activity and/or anti inflammatory activity and/or stem cell mobilizing activity. In particular, the method uses administration of an effective amount of the cyclized compound to provide CXCR4 antagonizing activity and/or stem cell mobilizing activity for slowing or halting the viral progression in an HIV infected patient, and for treating a cancer or an immunological disease that is mediated by or results from CXCR4 receptor activity.

The invention further encompasses methods for treating immunosuppression, accompanying the apheresis collection of peripheral blood stem cells, and inducing the mobilization of stem cells to regulate tissue repair. The described pharmacological properties include plasma protein binding and clearance suitable for low-dose and extended-release formulations, and the manufacturing aspect includes a mixed solid-/solution phase synthetic strategy for parallel-library manufacture, including cyclization and optional/alternative disulfide formation.

Claims Coverage

The independent claims provide two complementary method coverages: one for providing CXCR4 antagonizing activity, and one that also includes anti inflammatory activity and/or stem cell mobilizing outcomes for specified therapeutic use cases. Both independent claims are anchored by the same cyclized β-hairpin peptidomimetic framework with a required Cys4–Cys11 disulfide bond and defined residue constraints, with pharmaceutically acceptable salts as part of the scope.

Across the independent claims, the main claim coverage centers on administration of a defined cyclized β-hairpin peptidomimetic with a required Cys4–Cys11 disulfide, constrained residue choices at Xaa3/Xaa6/Xaa8/Xaa13/Xaa14/Xaa15 (including a proviso), and therapeutic use for providing CXCR4 antagonizing activity and specified outcomes/use cases including HIV viral progression slowing/halting, CXCR4-mediated cancers or immunological diseases, immunosuppression, peripheral blood stem cell apheresis, and regulating tissue repair via stem cell mobilization.

Stated Advantages

Documented Applications