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Ep 2376101 B1 (19) TZZ ¥_Z__T (11) EP 2 376 101 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 38/08 (2006.01) A61P 9/12 (2006.01) 02.12.2015 Bulletin 2015/49 A61P 9/00 (2006.01) C07K 7/14 (2006.01) (21) Application number: 09836520.8 (86) International application number: PCT/US2009/006719 (22) Date of filing: 28.12.2009 (87) International publication number: WO 2010/077339 (08.07.2010 Gazette 2010/27) (54) BETA-ARRESTIN EFFECTORS AND COMPOSITIONS AND METHODS OF USE THEREOF BETA-ARRESTIN-EFFEKTOREN UND ZUSAMMENSETZUNGEN UND ANWENDUNGSVERFAHREN DAFÜR EFFECTEURS DE LA BETA-ARRESTINE, COMPOSITIONS EN CONTENANT ET LEURS PROCÉDÉS D’UTILISATION (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR EP-A2- 0 498 361 WO-A2-90/03181 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL US-A- 3 932 624 US-A- 5 629 292 PT RO SE SI SK SM TR US-A- 5 958 884 US-A1- 2003 017 970 (30) Priority: 29.12.2008 US 141126 P • A. AUMELAS: "Studies on Angiotensin II and Analogs: Impact of Substitution in Position 8 on (43) Date of publication of application: Conformation and Activity", PROCEEDINGS OF 19.10.2011 Bulletin 2011/42 THE NATIONAL ACADEMY OF SCIENCES, vol. 82, no. 7, 1 April 1985 (1985-04-01), pages (73) Proprietor: Trevena, Inc. 1881-1885, XP55040722, ISSN: 0027-8424, DOI: King Of Prussia, PA 19406 (US) 10.1073/pnas.82.7.1881 • SAMANENJ ET AL: "EFFECTS OF D- AMINOACID (72) Inventors: SUBSTITUTION ON ANTAGONIST ACTIVITIES • YAMASHITA, Dennis OF ANGIOTENSIN II ANALOGUES", JOURNAL Wayne, PA 19087 (US) OF MEDICINAL CHEMISTRY, AMERICAN • CHEN, Xiao-Tao CHEMICAL SOCIETY, US, vol. 31, no. 3, 1 January Furlong, PA 18925 (US) 1988 (1988-01-01), pages 510-516, XP000867865, ISSN: 0022-2623, DOI: 10.1021/JM00398A005 (74) Representative: Bassil, Nicholas Charles et al • SCHOELKENS B A ET AL: "1,8 Disubstituted Kilburn & Strode LLP analogues of [Ile<5>] and [Val<5>]angiotensin II: 20 Red Lion Street difference in potency and specificity of London WC1R 4PJ (GB) angiotensin II antagonistic activity", HOPPE- SEYLER’S ZEITSCHRIFT FUR PHYSIOLOGISCHE CHEMIE 1976, vol. 357, no. 6, 1976, pages 825-838, XP002685146, ISSN: 0018-4888 • PATEL P.A., TILLEY D.G., ROCKMAN H.A: ’Beta- Arrestin-Mediated Signaling in the Heart’ CIRC J. vol. 72, no. 11, November 2008, pages 1725 - 1729 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 376 101 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 376 101 B1 Description RELATED APPLICATIONS 5 [0001] This application claims priority from U.S. Provisional Patent Application No. 61/141,126, filed on December 29, 2008. FIELD OF THE INVENTION 10 [0002] This application relates to a family of compounds acting as β-arrestin effectors. Such compounds may provide significant therapeutic benefit in the treatment of cardiovascular diseases, such as acute heart failure or acute hyper- tensive crisis. BACKGROUND 15 [0003] Drugs targeting GPCRs have been developed based on a signaling paradigm in which stimulation of the receptor by an agonist (e.g., angiotensin II) leads to activation of a heterotrimeric "G protein", which then leads to second mes- senger/down-stream signaling ( e.g., via diacylglycerol, inositol-triphosphate, calcium, etc...) and changes in physiological function (e.g., blood pressure and fluid homeostasis). There is a need for additional drugs that target GPCRs for treatment 20 of pathology associated with blood pressure and fluid homeostasis. [0004] The foregoing description of related art is not intended in any way as an admission that any of the documents described therein, including pending United States patent applications, are prior art to the present invention. Moreover, the description herein of any disadvantages associated with the described products, methods, and/or apparatus, is not intended to limit the invention. Indeed, aspects of the invention may include certain features of the described products, 25 methods, and/or apparatus without suffering from their described disadvantages. SUMMARY OF THE INVENTION [0005] According to some embodiments, the present disclosure provides for novelβ-aitestin effectors having the 30 structure: Xx-Yy-V al-Ww-Zz-Aa-Bb-Cc, [0006] In the structure above, variables Aa, Bb, Cc, Ww, Xx, Yy, and Zz can be selected from the respective groups 35 of chemical or biological moieties later described in the detailed description. β-arrestin effector derivatives and mimetics are also provided. Also provided are processes for preparing the compounds. [0007] According to some embodiments, the present disclosure provides for novelβ-arrestin effectors having the structure: 40 Xx-Arg-Val-Ww-Zz-His-Pro-Cc; or pharmaceutically acceptable salt, solvate, or hydrate thereof. In the structure above, variables Cc, Ww, Xx, and Zz can be selected from the respective groups of chemical or biological moieties later described in the detailed description. β-arrestin effector derivatives and mimetics are also provided. Also provided are processes for preparing the compounds. 45 [0008] According to some embodiments, the compounds of the present disclosure comprise the following formula: Sar-Arg-Val-Ww-Zz-His-Pro-Cc or pharmaceutically acceptable salt, solvate, or hydrate thereof. In the structure above, variables Cc, Ww, and Zz can 50 be selected from the respective groups of chemical or biological moieties later described in the detailed description. β- arrestin effector derivatives and mimetics are also provided. Also provided are processes for preparing the compounds. [0009] According to some embodiments, the compounds comprise the following formula: Sar-Arg-Val-Ww-OMTh-His-Pro-Cc, 55 or pharmaceutically acceptable salt, solvate, or hydrate thereof. In the structure above, variables Cc, and Ww can be selected from the respective groups of chemical or biological moieties later described in the detailed description.β- arrestin effector derivatives and mimetics are also provided. Also provided are processes for preparing the compounds. 2 EP 2 376 101 B1 [0010] According to some embodiments the composition comprises a peptide or peptide mimetic selected from the group consisting of a) a peptide or peptide mimetic comprising the sequence of 5 Xx-Yy-Val-Ww-Zz-Aa-Bb-Cc, wherein Xx is selected from the group consisting of null, sarcosine, N-methyl-L-alanine, N-methyl-D-alanine, N,N- dimethylglycine, L-aspartic acid, D-aspartic acid, L-glutamic acid, D-glutamic acid, N-methyl-L-aspartic acid, N- 10 methyl-L-glutamic acid, pyrrolid-1-ylacetic acid, and morpholin-4-ylacetic acid; Yy is selected from the group consisting of L-arginine, and L-lysine; Ww is selected from the group consisting of L-isoleucine, glycine, L-tyrosine, O-methyl-L-tyrosine, L-valine, L- phenylalanine, 3-hydroxy-L-tyrosine, 2,6-dimethyl-L-tyrosine, 3-fluoro-L-tyrosine, 4-fluorophenyl-L-analine, 2,6-dif- luoro-L-tyrosine, 3-nitro-L-tyrosine, 3,5-dinitro-L-tyrosine, 3,5-dibromo-L-tyrosine, 3-chloro-L-tyrosine, O-allyl-L-ty- 15 rosine, and 3,5-diiodo-L-tyrosine; Zz is selected from the group consisting of L-isoleucine, L-valine, L-tyrosine, L-glutamic acid, L-phenylalanine, L- histidine, L-lysine, L-arginine, O-methyl-L-threonine, D-alanine, and L-norvaline; Aa is selected from the group consisting of L-histidine, L-histidine-amide, and L-lysine; Bb is selected from the group consisting of L-proline, L-proline-amide, D-proline, and D-proline-amide; and 20 Cc is selected from the group consisting of null, L-isoleucine, L-isoleucine-amide, glycine, glycine-amide, L-alanine, L-alanine-amide, D-alanine, D-phenylalanine, L-norvaline; provided that when Xx is L-Aspartic acid, Cc is not L-phenylalanine; when Xx is sarcosine, Cc is not L-isoleucine; when Ww is glycine, Cc is not glycine; when Xx is sarcosine, and Zz is L-valine, Cc is not L-alanine; and when Xx is sarcosine, Ww is a L-tyrosine, and Zz is L-isoleucine, Cc is not L-alanine; 25 b) a peptide or peptide mimetic wherein the members of the sequence of the peptide or peptide mimetic maintain their relative positions as they appear in the sequence described in (a), wherein spacers of between 1 and 3 amino acids or amino acid analogues are inserted between one or more of the amino acids or amino acid analogues as described in (a) and wherein the total length of the peptide or peptide mimetic is between 6 and 25 amino acids and/or amino acid analogues; and 30 c) a peptide or peptide mimetic that is at least 70% identical to the peptide or peptide mimetics described in (a). [0011] According to other embodiments, the compositions comprise a peptide or peptide mimetic selected from the group consisting of 35 a) a peptide or peptide mimetic comprising the sequence of Xx-Arg-Val-Ww-Zz-His-Pro-Cc, wherein Xx is selected from the group consisting of sarcosine, N-methyl-L-alanine, N-methyl-D-alanine, N,N-dimeth- 40 ylglycine, L-aspartic acid, D-aspartic acid, L-glutamic acid, D-glutamic acid, N-methyl-L-aspartic acid, N-methyl-L- glutamic acid, pyrrolid-1-ylacetic acid, and morpholin-4-ylacetic acid; Ww is selected from the group consisting of L-isoleucine, glycine, L-tyrosine, O-methyl-L-tyrosine, L-valine, L- phenylalanine, 3-hydroxy-L-tyrosine, 2,6-dimethyl-L-tyrosine,
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