(51) International Patent Classification:
`(51) International Patent Classification:
`A61K 47/48 (2006.01)
`C07K 14/605 (2006.01)
`C07K 14/605 (2006.01)
`A61K 47148 (2006.01)
`C07D 233/64 (2006.01)
`C07D 233/64 (2006.01)
`.
`+
`us
`(21) International Application Number:
`(21) International Application Number:
`PCT/EP2010/069929
`PCT /EP20 I 0/069929
`
`(22)
`InternationalFiling Date:
`(22) International Filing Date:
`16 December 2010 (16.12.2010)
`16 December 2010 (16.12.2010)
`.
`English
`English
`English
`English
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property Organization
`(19) World Intellectual Property Organization
`International Bureau
`International Bureau
`
`(43) International Publication Date
`
`1111111111111111 IIIIII IIIII 111111111111111 II Ill 111111111111111 IIIII IIIII IIII IIIIIII IIII 11111111
`(10) International Publication Number
`(10) International Publication Number
`(43) International Publication Date
`WO 2011/073328 Al
`23 June 2011 (23.06.2011)
`WO 2011/073328 Al
`23 June 2011 (23.06.2011)
`PCT
`
`(81) Designated States (unless otherwise indicated, for every
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU,ID,IL,IN,IS, JP, KE, KG, KM,KN, KP,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM,ST, SV, SY, TH, TJ, TM, TN, TR,
`(25) Filing Language:
`(25) Filing Language:
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`(26) Publication Language:
`TT, TZ, VA, VG, US, UZ, VC, VN, ZA, ZM, ZW.
`(26) Publication Language:
`(84) Designated States (unless otherwise indicated, for every
`(30) Priority Data:
`(84) Designated States (unless otherwise indicated, for every
`(30) Priority Data:
`kind of regional protection available): ARIPO (BW, GH,
`EP
`09179390.1
`16 December 2009 (16.12.2009)
`kind of regional protection available): ARIPO (BW, GH,
`09179390.l
`EP
`16 December2009 (16.12.2009)
`GM, KE, LR, LS, MW, MZ, NA, SD,SL, SZ, TZ, UG,
`US
`61/288,601
`21 December 2009 (21.12.2009)
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`61/288,601
`US
`21 December 2009 (2l.l2.2009)
`ZM,ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU,TJ,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`(71) Applicant (for all designated States except US): NOVO
`(71) Applicant (for all designated States except US): NOVO
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`NORDISK A/S
`[DK/DK],; Novo Allé, DK-2880
`NORDISK A/S
`[DK/DK]; Novo Alie, DK-2880
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK,MT, NL, NO, PL, PT, RO, RS, SE, SL SK,
`Bagsveerd (DK).
`Bagsv.erd (DK).
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`(72)
`Inventors; and
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`(72) Inventors; and
`GW, ML, MR, NE, SN, TD, TG).
`(75)
`Inventors/Applicants (for US only): KODRA, Jénos,
`GW, ML, MR, NE, SN, TD, TG).
`(75) Inventors/Applicants (for US only): KODRA, Janos,
`Tibor [DK/DK]; Novo Allé, DK-2880 Bagsvaerd (DK). Published:
`Tibor [DK/DK]; Novo Alie, DK-2880 Bagsvaerd (DK).
`Published:
`MADSEN, Johnny [DK/DK]; Novo Allé, DK-2880 __
`wpe
`.
`MADSEN, Johnny [DK/DK]; Novo Alie, DK-2880
`Bagsvaerd (DK).
`with international search report (Art. 21(3))
`with international search report (Art. 21 (3))
`Bagsvaerd (DK).
`— with sequence listing part ofdescription (Rule 5.2(a))
`with sequence listing part of description (Rule 5.2(a))
`
`(54) Title: GLP-1 RECEPTOR AGONIST COMPOUNDSWITH A MODIFIED N-TERMINUS
`(54) Title: GLP-l RECEPTOR AGONIST COMPOUNDS WITH A MODIFIED N-TERMINUS
`(57) Abstract: The invention relates to GLP-1 receptor agonist compounds with a modified N- terminus. The compoundsare of
`(57) Abstract: The invention relates to GLP-l receptor agonist compounds with a modified N- terminus. The compounds are of
`the formula Chem. 1: Y-Z-P, wherein P represents a fragment of a GLP-1 receptor agonist peptide lacking the two N-terminal
`the formula Chem. I: Y-Z-P, wherein P represents a fragment of a GLP-l receptor agonist peptide lacking the two N-terminal
`amino acid residues; and Y-Z represents novel His-Ala mimetics. Examples of GLP-1 receptor agonist compoundsare derived
`amino acid residues; and Y-Z represents novel His-Ala mimetics. Examples of GLP-l receptor agonist compounds are derived
`from human GLP-1 (7-37), exendin-4(1-39), or GLP-1 A (1-37). The invention also relates to derivatives of these compounds, in
`from human GLP-l (7-37), exendin-4(1-39), or GLP-l A (l-37). The invention also relates to derivatives of these compounds, in
`particular compounds with one or more albumin bindingside chains capable of protracting the duration of action in vivo of these
`particular compounds with one or more albumin binding side chains capable of protracting the duration of action in vivo of these
`compounds. The peptides and derivatives of the invention have a good potency, a protracted pharmacokinetic profile, are stable
`compounds. The peptides and derivatives of the invention have a good potency, a protracted pharmacokinetic profile, are stable
`against degradation by gastro intestinal enzymes, and/or have a high oral bioavailability. These properties are of importance in the
`against degradation by gastro intestinal enzymes, and/or have a high oral bioavailability. These properties are of importance in the
`development of GLP-1 receptor agonist compounds for subcutaneous, intravenous, and/or in particular oral administration. The
`development of GLP-l receptor agonist compounds for subcutaneous, intravenous, and/or in particular oral administration. The
`invention also relates to intermediate products for use in the preparation of the GLP-1 receptor agonist compoundsof the inven-
`invention also relates to intermediate products for use in the preparation of the GLP- l receptor agonist compounds of the inven(cid:173)
`tion.
`tion.
`
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`;;;;;;;;;;;;;;
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`MPI EXHIBIT 1057 PAGE 1
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`MPI EXHIBIT 1057 PAGE 1
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`DR. REDDY’S LABORATORIES, INC.
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`WO 2011/073328
`
`PCT /EP2010/069929
`
`GLP-1 RECEPTOR AGONIST COMPOUNDS WITH A MODIFIED N-TERMINUS
`
`FIELD OF THE INVENTION
`
`The present invention relates to analogues and derivatives of GLP-1 receptor
`
`agonist peptides, and their pharmaceutical use. In the GLP-1 receptor agonist peptides of the
`
`5
`
`invention, such as Glucagon-Like Peptide-1 (GLP-1 ), exendins and analogues thereof, the
`
`two N-terminal amino acids have been replaced by N-terminal mimetics.
`
`INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING
`
`The Sequence Listing, entitled "SEQUENCE LISTING", is 1770 bytes, was created
`
`10
`
`on 01-DEC-2010, and is incorporated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`WO 2004/067548 A2 relates to chemically modified metabolites of regulatory
`
`peptides and methods of producing and using same.
`
`Liraglutide, a GLP-1 derivative for once daily administration which is marketed by
`
`15
`
`Novo Nordisk A/S, is disclosed in Example 37 of WO 98/08871.
`
`Semaglutide, a GLP-1 derivative for once weekly administration which is under
`
`development by Novo Nordisk A/S, is disclosed in Example 4 of WO 06/097537.
`
`SUMMARY OF THE INVENTION
`
`The invention relates to GLP-1 receptor agonist compounds comprising a modified
`
`20
`
`N-terminus.
`
`Preferred compounds have the formula Chem. 1: Y-Z-P, wherein P represents a
`
`fragment of a GLP-1 receptor agonist peptide lacking the N-terminus; and Y-Z represents a
`
`group mimicing the N-terminus of the peptide. The new N-terminal is preferably a His-Ala, a
`
`His-Gly, and/or a His-Ser mimetic.
`
`25
`
`More in particular the invention relates to a GLP-1 receptor agonist peptide having
`
`the formula Chem. 1: Y-Z-P, wherein P represents a fragment of a GLP-1 receptor agonist
`
`peptide lacking the two N-terminal amino acid residues; Z represents a group of the formula
`
`Chem. 2:
`
`, wherein W represents a group of formula Chem. 3:
`
`* I
`R1-C-R2
`I
`*
`
`wherein R1 and R2 independently represent (i) hydrogen, alkyl, aryl, heterocyclyl, heteroaryl,
`
`MPI EXHIBIT 1057 PAGE 2
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`MPI EXHIBIT 1057 PAGE 2
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`
`PCT /EP2010/069929
`
`2
`
`halogen, hydroxyl, hydroxylalkyl, cyano, amino, aminoalkyl, carboxyl, carboxylalkyl, alkoxy,
`
`aryloxy, carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, or aryl
`
`sulfonyl, or R 1 and R2 together form (ii) cyclo alkyl, heterocyclyl, or heteroaryl; and Y
`
`X
`
`R12
`
`x/ 1/2
`'-II... 2
`R114-x Q-NR-*
`
`3
`
`4
`
`5
`
`, or Chem. 5:
`
`represents a group of formula Chem. 4:
`
`R14
`
`R13-Q
`
`5
`
`Q -NR-*
`, wherein X 1 is N, 0, or S; X2 , X 3 , X4 , and X 5 independently
`represent C, or N, with the proviso that at least one of X 2 , X 3 , X4 and X 5 is C; R 11, R 12, R 13,
`and R14 independently represent hydrogen, alkyl, aryl, heterocyclyl, heteroaryl, halogen,
`
`hydroxyl, hydroxylalkyl, cyano, amino, aminoalkyl, carboxyl, carboxylalkyl, alkoxy, aryloxy,
`
`carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, or aryl sulfonyl;
`
`10 Q represents a bond, or a group of formula
`
`Chem. 6:*-(C(R15)(R16))q-*, wherein q is 1-6, and R15and R16 independently of each other
`
`and independently for each value of q represent hydrogen, alkyl, carboxyl, or hydroxyl; and R
`
`represents hydrogen, or alkyl; or a pharmaceutically acceptable salt, amide, or ester thereof.
`
`The invention also relates to a derivative of this peptide, and a pharmaceutically
`
`15
`
`acceptable salt, amide, or ester thereof.
`
`The invention also relates to the pharmaceutical use of these compounds,
`
`preferably for the treatment and/or prevention of all forms of diabetes and related diseases,
`
`such as eating disorders, cardiovascular diseases, gastrointestinal diseases, diabetic
`
`complications, critical illness, and/or polycystic ovary syndrome; and/or for improving lipid
`
`20
`
`parameters, improving 13-cell function, and/or for delaying or preventing diabetic disease
`
`progression.
`
`Finally, the invention relates to intermediate products corresponding to the new N(cid:173)
`
`terminus, as well as to the peptide fragments, i.e. before attachment of the new N-terminus,
`
`both relevant for the preparation of the peptides of the invention.
`
`25
`
`The peptides and derivatives of the invention are biologically active, preferably of a
`
`high potency. Also, or alternatively, they have a protracted pharmacokinetic profile. Also, or
`
`alternatively, they are stable against degradation by gastro intestinal enzymes. Also, or
`
`alternatively, they have a high oral bioavailability. These properties are of importance in the
`
`MPI EXHIBIT 1057 PAGE 3
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`MPI EXHIBIT 1057 PAGE 3
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`
`PCT /EP2010/069929
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`3
`
`development of next generation GLP-1 compounds for subcutaneous, intravenous, and/or in
`
`particular oral administration.
`
`DESCRIPTION OF THE INVENTION
`
`The invention relates to a GLP-1 receptor agonist peptide having the formula Chem.
`
`5
`
`1: Y-Z-P, wherein P represents a fragment of a GLP-1 receptor agonist peptide lacking the
`
`two N-terminal amino acid residues; Z represents a group of the formula Chem.
`
`2:
`
`, wherein W represents a group of formula Chem. 3:
`
`* I
`R1-C-R2
`I
`*
`
`, wherein
`
`R1 and R2 independently represent (i) hydrogen, alkyl, aryl, heterocyclyl, heteroaryl,
`
`halogen, hydroxyl, hydroxylalkyl, cyano, amino, aminoalkyl, carboxyl, carboxylalkyl, alkoxy,
`
`10
`
`aryloxy, carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, or aryl
`
`sulfonyl, or R 1 and R2 together form (ii) cyclo alkyl, heterocyclyl, or heteroaryl; and Y
`
`X
`R12
`x/1~
`... I I 2
`3
`R11_.\\-
`"'f-.1....
`X4-X5 Q-NR- *
`, or Chem. 5:
`
`represents a group of formula Chem. 4:
`
`R14
`
`R13-Q
`
`Q -NR-*
`, wherein X 1 is N, 0, or S; X2 , X 3 , X4 , and X 5 independently
`represent C, or N, with the proviso that at least one of X 2 , X 3 , X4 and X 5 is C; R 11, R 12, R 13,
`and R 14 independently represent hydrogen, alkyl, aryl, heterocyclyl, heteroaryl, halogen,
`
`15
`
`hydroxyl, hydroxylalkyl, cyano, amino, aminoalkyl, carboxyl, carboxylalkyl, alkoxy, aryloxy,
`
`carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, or aryl sulfonyl;
`
`Q represents a bond, or a group of formula
`
`Chem. 6:*-(C(R15)(R16))q-*, wherein q is 1-6, and R15and R16 independently of each other
`
`20
`
`and independently for each value of q represent hydrogen, alkyl, carboxyl, or hydroxyl; and R
`
`represents hydrogen, or alkyl; or a pharmaceutically acceptable salt, amide, or ester thereof.
`
`In a first aspect, R1 and R2 do not both represent hydrogen, and the invention
`
`accordingly relates to a GLP-1 receptor agonist peptide having the formula Chem. 1: Y-Z-P,
`
`wherein P represents a fragment of a GLP-1 receptor agonist peptide lacking the two N-
`
`MPI EXHIBIT 1057 PAGE 4
`
`MPI EXHIBIT 1057 PAGE 4
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`

`WO 2011/073328
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`PCT /EP2010/069929
`
`4
`
`terminal amino acid residues; Z represents a group of the formula Chem. 2:
`
`wherein W represents a group of formula Chem. 3:
`
`* I
`R1-C-R2
`I
`*
`
`, wherein
`
`R1 and R2
`
`independently represent (i) hydrogen, alkyl, aryl, heterocyclyl, heteroaryl, halogen, hydroxyl,
`
`hydroxylalkyl, cyano, amino, aminoalkyl, carboxyl, carboxylalkyl, alkoxy, aryloxy,
`
`5
`
`carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, or aryl sulfonyl,
`
`or R 1 and R2 together form (ii) cyclo alkyl, heterocyclyl, or heteroaryl, with the proviso that
`
`(iii) R1 and R2 do not both represent hydrogen; and Y represents a group of formula Chem.
`
`-0
`
`R14
`~\
`,,._N
`
`R13
`
`R12
`X
`x/1/2
`'-11....2
`3
`R114-x Q-NR-*
`
`4
`
`5
`
`Q -NR-*
`, wherein X 1 is N, 0, or S;
`, or Chem. 5:
`4:
`X2 , X3 , X4 , and X 5 independently represent C, or N, with the proviso that at least one of X2 ,
`X 3 , X4 and X 5 is C; R11, R12, R13, and R14 independently represent hydrogen, alkyl, aryl,
`heterocyclyl, heteroaryl, halogen, hydroxyl, hydroxylalkyl, cyano, amino, aminoalkyl,
`
`10
`
`carboxyl, carboxylalkyl, alkoxy, aryloxy, carboxamide, substituted carboxamide, alkyl ester,
`
`aryl ester, alkyl sulfonyl, or aryl sulfonyl; Q represents a bond, or a group of formula
`
`Chem. 6:*-(C(R15)(R16))q-*, wherein q is 1-6, and R15and R16 independently of each other
`
`15
`
`and independently for each value of q represent hydrogen, alkyl, carboxyl, or hydroxyl; and R
`
`represents hydrogen, or alkyl; or a pharmaceutically acceptable salt, amide, or ester thereof.
`
`In a second aspect, R1 and R2 may both represent hydrogen, and Q-NR-* is not
`
`attached to a nitrogen atom of Chem. 4.
`
`In a third aspect, R1 and R2 may both represent hydrogen, and Q-NR-* is attached
`
`20
`
`to a carbon atom of Chem. 4.
`
`The invention also relates to a derivative of each of these peptides, and to
`
`pharmaceutically acceptable salts, amides, or esters thereof.
`
`The invention also relates to the pharmaceutical use of these compounds,
`
`preferably for the treatment and/or prevention of all forms of diabetes and related diseases,
`
`25
`
`such as eating disorders, cardiovascular diseases, gastrointestinal diseases, diabetic
`
`complications, critical illness, and/or polycystic ovary syndrome; and/or for improving lipid
`
`MPI EXHIBIT 1057 PAGE 5
`
`MPI EXHIBIT 1057 PAGE 5
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`WO 2011/073328
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`PCT /EP2010/069929
`
`5
`
`parameters, improving 13-cell function, and/or for delaying or preventing diabetic disease
`
`progression.
`
`Finally, the invention relates to intermediate products corresponding to the new N(cid:173)
`
`terminus, as well as to the peptide fragments, i.e. before attachment of the new N-terminus,
`
`5
`
`both relevant for the preparation of the peptides of the invention.
`
`In what follows, Greek letters may be represented by their symbol or the
`
`corresponding written name, for example: a= alpha; ~ = beta; E = epsilon; y = gamma; m =
`
`omega; etc. Also, the Greek letter ofµ my be represented by "u", e.g. in µl=ul, or in µM=uM.
`
`An asterisk (*) in a chemical formula designates i) a point of attachment, ii) a radical,
`
`10
`
`and/or iii) an unshared electron.
`
`GLP-1 receptor aqonist
`
`The GLP-1 receptor agonist compounds of the invention may be derived, or are
`
`derivable, from human GLP-1(7-37), exendin-4(1-39), and/or GLP-1A(1-37). The amino acid
`
`15
`
`sequences of these peptides may be found in the UniProt Knowledgebase (UniProtKB) -
`
`SwissProt section (www.uniprot.org) with the following accession numbers, sequence
`
`identifiers, and sequence names: UNIPROT:P01275_8, GLUC_HUMAN, Glucagon-like
`
`peptide 1 (7-37); UNIPROT:P26349_3, EXE4_HELSU, Exendin-4, or exenatide; and
`
`UNIPROT:O42143_5, GLUC1_XENLA, Glucagon-like peptide 1A; respectively.
`
`20
`
`The sequences of the corresponding fragments lacking the two N-terminal amino
`
`acids, viz. GLP-1 (9-37), exendin-4(3-39), and GLP-1A(3-37), are included in the appended
`
`sequence listing as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively.
`
`Another example of a GLP-1 receptor agonist fragment from which the compounds
`
`of the invention may be derived, or are derivable, is the peptide designated exendin-3(3-39)
`
`25
`
`which is the D3 analogue of SEQ ID NO: 2, i.e. identical to SEQ ID NO: 2 except for having
`
`aspartic acid (D, Asp) at position 3, the first amino acid residue.
`
`The sequence of the GLP-1 receptor may be found in the UniprotKB database
`
`referred to above with the following accession number, identifier, and name:
`
`UNI PROT: P43220, GLP1 R_HUMAN, Glucagon-like peptide 1 receptor, GLP-1 receptor,
`
`30
`
`GLP-1-R, orGLP-1R.
`
`The term "GLP-1 receptor agonist" as used herein refers to a compound which is an
`
`agonist of the human GLP-1 receptor, i.e. a compound that stimulates the formation of cAMP
`
`in a medium containing the human GLP-1 receptor. GLP-1 receptor agonism, or potency, is
`
`determined as described below, in the section headed "Potency", see also Example 13
`
`35
`
`herein.
`
`MPI EXHIBIT 1057 PAGE 6
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`
`6
`
`Amino acids and peptides
`
`The term "peptide", as e.g. used in the context of the GLP-1 receptor agonist
`
`peptides of the invention, refers to a compound which comprises a series of amino acids
`
`5
`
`intereconnected by amide (or peptide) bonds.
`
`In a particular embodiment the peptide is to a large extent, or predominantly,
`
`composed of amino acids interconnected by amide bonds (e.g., at least 50%, 60%, 70%,
`
`80%, or at least 90%, by molar mass). In another particular embodiment the peptide consists
`
`of amino acids interconnected by peptide bonds.
`
`10
`
`The peptides of the invention comprise at least five constituent amino acids
`
`connected by peptide bonds. In particular embodiments the peptide comprises at least 10,
`
`preferably at least 15, more preferably at least 20, even more preferably at least 25, or most
`
`preferably at least 28 amino acids.
`
`In particular embodiments, the peptide is composed of at least five constituent
`
`15
`
`amino acids, preferably composed of at least 10, at least 15, at least 20, at least 25, or most
`
`preferably composed of at least 28 amino acids.
`
`In additional particular embodiments, the peptide is a) composed of, orb) consists
`
`of, i) 29, ii) 30, iii) 31, or iv) 32 amino acids.
`
`In still further particular embodiments, the peptide is a) composed of, orb) consists
`
`20
`
`of, i) 33, ii) 34, iii) 35, or iv) 36 amino acids.
`
`In a still further particular embodiment the peptide consists of amino acids
`
`interconnected by peptide bonds.
`
`Amino acids are molecules containing an amine group and a carboxylic acid group,
`
`and, optionally, one or more additional groups, often referred to as a side chain.
`
`25
`
`The term "amino acid" includes proteogenic amino acids (encoded by the genetic
`
`code, including natural amino acids, and standard amino acids), as well as non-proteogenic
`
`(not found in proteins, and/or not coded for in the standard genetic code), and synthetic
`
`amino acids. Thus, the amino acids may be selected from the group of proteinogenic amino
`
`acids, non-proteinogenic amino acids, and/or synthetic amino acids.
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`30
`
`Non-limiting examples of amino acids which are not encoded by the genetic code
`
`are gamma-carboxyglutamate, ornithine, and phosphoserine. Non-limiting examples of
`
`synthetic amino acids are the D-isomers of the amino acids such as D-alanine and D-leucine,
`
`Aib (cx-aminoisobutyric acid), ~-alanine, and des-amino-histidine (desH, alternative name
`
`imidazopropionic acid, abbreviated Imp).
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`In what follows, all amino acids for which the optical isomer is not stated is to be
`
`understood to mean the L-isomer (unless otherwise specified).
`
`GLP-1 receptor agonist peptides, fragments, analogues, residue numbering, identity
`
`5
`
`A "GLP-1 receptor agonist peptide" is a peptide as defined above, and also a GLP-1
`
`receptor agonist as defined above.
`
`The peptides of the invention are GLP-1 receptor agonist peptides.
`
`Additional examples of GLP-1 receptor agonist peptides are the following known
`
`compounds: Human GLP-1(7-37), exendin-4(1-39), exendin-3(1-39), and GLP-1A(1-37).
`
`10
`
`In a particular embodiment, the GLP-1 receptor agonist compound of the invention
`
`may be derived, or is derivable, from any one or more of these known GLP-1 receptor
`
`agonist peptides.
`
`The term "fragment" as it refers to a GLP-1 receptor agonist peptide means a
`
`peptide which is shorter than the peptide referred to.
`
`15
`
`In a particular embodiment corresponding to the definition of group P in formula I,
`
`the fragment lacks the two N-terminal amino acids as compared to the corresponding full(cid:173)
`
`length peptide being a GLP-1 receptor agonist.
`
`In another particular embodiment this particular fragment is not in itself a GLP-1
`
`receptor agonist, due to a i) substantial, ii) preferably almost complete, or iii) more preferably
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`20
`
`for all practical purposes complete, loss of biological activity (i.e., GLP-1 receptor agonism).
`
`Particular examples of P (fragments of a GLP-1 receptor agonist peptide lacking the
`
`two N-terminal amino acid residues) are the following: GLP-1 (9-37), exendin-4(3-39), and
`
`GLP-1A(3-37), which are included in the appended sequence listing as SEQ ID NO: 1, SEQ
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`ID NO: 2, and SEQ ID NO: 3, respectively. Another example of Pis exendin-3(3-39) which is
`
`25
`
`variant D3 of SEQ ID NO: 2.
`
`In the sequence listing, the first amino acid residue of the fragment of GLP-1 (9-37)
`
`(SEQ ID NO: 1 ), which is glutamic acid, is assigned no. 1. However, in what follows -
`
`according to established practice in the art - this glutamic acid residue is referred to as no. 9,
`
`and subsequent amino acid residues are numbered accordingly, ending with glycine no. 37.
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`30
`
`Likewise, in the sequence listing, the first amino acid residue of exendin-4(3-39)
`
`(SEQ ID NO: 2), which is also glutamic acid, is assigned no. 1. However, in what follows -
`
`according to established practice in the art - this glutamic acid residue is referred to as no. 3,
`
`and subsequent amino acid residues are numbered accordingly, ending with serine as no.
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`39.
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`Likewise, in the sequence listing, the first amino acid residue of GLP-1A(3-37) (SEQ
`
`ID NO: 3), which is aspartic acid, is assigned no. 1. However, in what follows - according to
`
`established practice in the art - this aspartic acid residue is referred to as no. 3, and
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`subsequent amino acid residues are numbered accordingly, ending with serine as no. 37.
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`5
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`Therefore, generally, any reference herein to an amino acid residue number or a
`
`position number in the context of the peptides of SEQ ID NO: 1, 2, or 3 or analogues thereof
`
`is to the sequence starting with Glu at position 9, Glu at position 3, or Asp at position 3,
`
`respectively; and ending with Gly at position 37, Ser at position 39, or Ser at pas. 37,
`
`respectively.
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`10
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`Additional particular examples of P are analogues of SEQ ID NO: 1, SEQ ID NO: 2,
`
`and/or SEQ ID NO: 3.
`
`An "analogue" as used herein in the context of SEQ ID NO: 1, 2, or 3 refers to a
`
`peptide, or a compound, which is a variant of any one or more of SEQ ID NO: 1, 2, or 3.
`
`In a particular embodiment, the analogue of SEQ ID NO: 1 refers to a modification of
`
`15
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`SEQ ID NO: 1 in which a number of amino acid residues have been exchanged as compared
`
`to SEQ ID NO: 1. These exchanges, or modifications, may represent, independently, one or
`
`more amino acid substitutions, additions, and/or deletions. Additions at the N-terminus are,
`
`however, preferably excluded. Analogues of SEQ ID NO: 2, and SEQ ID NO: 3 are defined
`
`similarly, by analogy to the definition of analogues of SEQ ID NO: 1.
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`20
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`Analogues may be described by reference to a reference sequence, the number of
`
`the amino acid residue in the reference sequence corresponding to the one which is
`
`modified, i.e., its position, and to the actual modification.
`
`In particular embodiments, the reference sequence is i) GLP-1(9-37) (SEQ ID NO:
`
`1); ii) exendin-4(3-39) (SEQ ID NO: 2); or iii) GLP-1A(3-37) (SEQ ID NO: 3).
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`25
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`The following are non-limiting, illustrative examples of suitable analogue
`
`nomenclature, as used herein:
`
`Ng -[-{2-[2-( 1 H-I m idazol-4-yl)-ethylcarbamoyl]-2-methyl-propionyl}-
`[Lys 18,Glu22,Gln34]GLP-1 (9-37) peptide is a GLP-1 receptor agonist peptide of the invention
`derivable from GLP-1 (9-37) (SEQ ID NO: 1 ), i.e. Pin Chem. 1 is an analogue of SEQ ID NO:
`
`30
`
`1, viz. the analogue in which the serine at position 18 has been substituted with lysine, the
`
`glycine at position 22 has been substituted with glutamic acid, and the lysine at position 34
`
`has been substituted with glutamine;
`, Lys 36]G LP-
`Ng -{2-[2-( 1 H-I m idazol-4-yl)propylcarbamoyl]-2-methyl-propionyl}-[Glu 30
`1 (9-37)Glu 38-peptide is a GLP-1 receptor agonist peptide of the invention derivable from
`
`35 GLP-1 (9-37) (SEQ ID NO: 1 ), i.e. Pin Chem. 1 is an analogue of SEQ ID NO: 1, viz. the
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`analogue in which the alanine at position 30 has been substituted with glutamic acid, the
`
`arginine at position 36 has been substituted with lysine, and a glutamic acid has been added
`
`at the C-terminus, viz. at position 38; and
`N3-{2-[2-(1 H-lmidazol-4-yl)-methylcarbamoyl]-2-methyl-propionyl}-
`[Arg 17,Arg20,Arg 33,Lys 38]GLP-1A(3-37)-peptide is a GLP-1 receptor agonist peptide of the
`invention derivable from GLP-1A(3-37) (SEQ ID NO: 3), i.e. Pin Chem. 1 is an analogue of
`
`5
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`SEQ ID NO: 3, viz. the analogue in which the lysines at position 17, 20, and 33 have been
`
`substituted with arginine, and a lysine has been added at the C-terminus, viz. at position 38.
`
`This peptide, by the way, is also derivable from SEQ ID NO: 1, and it can therefore
`
`10
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`also be designated as analogue (17T, 18Q, 19Q, 21 D, 22E, 23R, 26R, 30D, 331, 34N, 36G,
`
`37P, 38S, 39R, 40E, 411,421, 43S, 44K) of GLP-1(9-37) (SEQ ID NO: 1), having {2-[2-(1H(cid:173)
`lmidazol-4-yl)-methylcarbamoyl]-2-methyl-propionyl}- attached to the N-terminus, N9
`
`.
`
`As another example, a GLP-1 receptor agonist peptide of the invention which
`
`"comprises at least one of the following substitutions as compared to GLP-1 (9-37) (SEQ ID
`
`15
`
`NO: 1): 18K; 22E; 30E; 31H; 34Q,R; 36K; 37K; and/or38E" refers to a GLP-1 receptor
`
`agonist peptide in which P of Chem. 1 is considered an analogue of SEQ ID NO: 1, which
`
`analogue has a lysine at position 18, a glutamic acid at position 22, a glutamic acid at
`
`position 30, a histidine at position 31, a glutamine at position 34, a lysine at position 36, a
`
`lysine at position 37, and/or a glutamic acid at position 38, and which analogue may
`
`20
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`comprise further modifications as compared to SEQ ID NO: 1.
`
`As is apparent from the above examples, amino acid residues may be identified by
`
`their full name, their one-letter code, and/or their three-letter code. These three ways are fully
`
`equivalent.
`
`The expressions "a position equivalent to" or "corresponding position" may be used
`
`25
`
`to characterise the site of modification in a modified GLP-1 receptor agonist peptide
`
`sequence by reference to any one or more of SEQ ID NO: 1, 2, or 3. Equivalent or
`
`corresponding positions, as well as the number of modifications, are easily deduced, e.g. by
`
`simple handwriting and eyeballing; and/or a standard protein or peptide alignment program
`
`may be used, such as "align" which is a Needleman-Wunsch alignment. The algorithm is
`
`30
`
`described in Needleman, S.B. and Wunsch, C.D., (1970), Journal of Molecular Biology, 48:
`
`443-453, and the align program by Myers and W. Miller in "Optimal Alignments in Linear
`
`Space" CABIOS (computer applications in the biosciences) (1988) 4:11-17. For the
`
`alignment, the default scoring matrix BLOSUM50 and the default identity matrix may be
`
`used, and the penalty for the first residue in a gap may be set at -12, or preferably at -10, and
`
`35
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`the penalties for additional residues in a gap at -2, or preferably at -0.5.
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`This algorithm may also suitably be used for determining the degree of identity of
`
`the P-group of a GLP-1 receptor agonist peptide of the invention to each of SEQ ID NO: 1, 2,
`
`and 3, e.g. with a view to determining which of these three sequences has the highest
`
`percentage of identity to the P-group in question, and thus for determining the number of
`
`5
`
`amino acid residues that have been exchanged as compared to the closest related sequence
`
`of SEQ ID NOs: 1-3 (the one with the highest percentage of identity). If the percentages of
`
`identity of a given P group of a GLP-1 receptor agonist of the invention to SEQ ID NO: 1, 2,
`
`and 3, respectively, should happen to be the same, any of those having the same highest
`
`percentage of identity may be used for the determination.
`
`10
`
`An example of such alignment is inserted hereinbelow, in which sequence no. 1 is
`
`SEQ ID NO: 1, and sequence no. 2 is SEQ ID NO: 3:
`
`# 1: GLP_1(9-37)
`# 2: GLP-1A(3-37)
`# Matrix: EBLOSUM62
`# Gap_penalty: 10.0
`# Extend_penalty: 0.5
`# Length: 35
`# Identity:
`# Similarity:
`# Gaps:
`# Score: 92.0
`
`18/35 (51.4%)
`22/35 (62. 9%)
`6/35 (17.1%)
`
`15
`
`20
`
`GLP_1(9-37)
`
`1 EGTFTSDVSSYLEGQAAKEFIAWLVKGRG------
`
`25
`
`GLP-1A(3-37)
`
`11111111 = -
`- I= - = 111111 - 11 = -
`I -
`-
`1 EGTFTSDVTQQLDEKAAKEFIDWLINGGPSKEIIS
`
`29
`
`35
`
`The above alignment is just for illustration, as typically an analogue of one of SEQ
`
`ID NOs: 1, 2, or 3 will be compared with either of these reference sequences.
`
`In case of analogues comprising non-natural amino acids such as Imp, and/or Aib
`
`30
`
`being included in the sequence, these may, for alignment purposes, be replaced with X. If
`
`desired, X can later be manually correcte