Novo Nordisk A/s

Lau, Jesper

Jacob Kofoed

Patrick William Garibay

Jesper F Lau

Lars Linderoth

Thomas Kruse

Janos Tibor Kodra

Jane Spetzler

Per Sauerberg

Steffen Reedtz-Runge

Birgit Wieczorek

Ingrid Pettersson

Paw Bloch

Christian Wenzel Tornoee

Henning Thoegersen

Kjeld Madsen

Frantisek Hubalek

Lauge Schaeffer

Flemming Seier Nielsen

Henning Thøgersen

János Tibor Kodra

Christian Wenzel Tornoe

Kirsten Raun

Christian Wenzel Tornøe

Lauge Schäffer

Alice Ravn Madsen

Rikke Bjerring Andersen

Anette Sams Nielsen

Carsten Engaard Stidsen

Johannes Fels

Cecilia Nilsson

Christoph Kalthoff

Birgit Wiezorek

Steffen Runge

Patric Garibay

The invention relates to a derivative of a GLP-1 analogue of a general Formula I, which derivative comprises a side chain attached to a Lys residue at position 34, 35, 36, 37, or 38 of the GLP-1 analogue, which side chain comprises a Branched linker, a 1and a 2Protractor selected from C18 diacid, C20 diacid, and sulfonic acid C16, and at least one Linker element-1 incorporating ethylene glycol units. Linker element-1 may be incorporated in an optional Pre-linker, and/or in a 1or 2Post-linker. The invention also relates to novel GLP-1 analogues, novel side chain intermediate products and their manufacture and use to prepare derivatives of biologically active peptides and proteins, as well as pharmaceutical compositions and medical uses of the analogues and derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

GLP-1 derivatives and uses thereof

The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue and a second K residue, at positions corresponding to position 26, and 37, respectively, of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of eight amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1: HOOC&#x2014;(CH)&#x2014;CO&#x2014;*, and Chem. 2: HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;*, in which x is an integer in the range of 8-16, and y is an integer in the range of 6-13; and the linker comprises Chem. 3: *&#x2014;NH&#x2014;(CH)&#x2014;CH[(CH)&#x2014;NRR]&#x2014;CO&#x2014;*, which is connected at its CO&#x2014;* end to the epsilon amino group of the first or the second K residue of the GLP-1 analogue, and wherein q is an integer in the range of 0-5, Rand Rindependently represent *&#x2014;H or *&#x2014;CH, and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptide and linker intermediates. The derivatives are potent, stable, protracted, and suitable for oral administration.

Double-acylated GLP-1 derivatives

The invention relates to a derivative of a GLP-1 peptide, which peptide comprises a first K residue and a second K residue, at positions corresponding to position 26, and 34, respectively, of GLP-1(7-37) (SEQ ID NO:1), and a maximum of eight amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is Chem. 2: HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;*, in which y is an integer in the range of 6-13; and the linker comprises Chem. 3a: *&#x2014;NH&#x2014;(CH)&#x2014;CH[(CH)&#x2014;NRR]&#x2014;CO&#x2014;*, wherein q is an integer in the range of 0-5, Rand Rindependently represent *&#x2014;H or *&#x2014;CH, and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptide and linker intermediates. The derivatives are potent, stable, protracted, and suitable for oral administration.

The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 27 of GLP-1(7-37) (SEQ ID NO: 1); a second K residue at a position corresponding to position T of GLP-1(7-37), where T is an integer in the range of 7-37 except 18 and 27; and a maximum of ten amino acid changes as compared to GLP-1(7-37); wherein the first K residue is designated K, and the second K residue is designated K; which derivative comprises two albumin binding moieties attached to Kand K, respectively, via a linker, wherein the albumin binding moiety comprises a protracting moiety selected from HOOC&#x2014;(CH)&#x2014;CO&#x2014; and HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;; in which x is an integer in the range of 6-16, and y is an integer in the range of 3-17; wherein the linker comprises an element of the formula &#x2014;NH&#x2014;(CH)&#x2014;(O&#x2014;(CH))&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel GLP-1 analogues. The derivatives are suitable for oral administration.

The invention relates to GLP-1 analogues and derivatives having a Trp at a position corresponding to position 8 of GLP-1(7-37), and their pharmaceutical use e.g. in the treatment of type 2 diabetes. These Trp8 compounds are very stable against degradation by DPP-IV, while maintaining the capability to bind to and activate the GLP-1 receptor. The derivatives have one or two substituents (P-L) attached to a Lys residue of the GLP-1 analogue via an optional Branching group (B), wherein P is a Protracting moiety such as a fatty diacid, and L is a linker consisting of one or more linker elements such as, for example, 8-amino-3,6-dioxaoctanoic acid. Examples of compounds of the invention include the 8W variants of liraglutide and dulaglutide. The invention also relates to a method for the fully recombinant preparation of 8W GLP-1 analogues and derivatives which is more simple and thereby cheaper as compared to the preparation of known GLP-1 analogues that have been DPP-IV stabilised by inclusion of one or more non-coded amino acids.

The invention relates to a derivative of a GLP-1 peptide, which peptide comprises a first Lys residue at a position corresponding to position 36 of GLP-1(7-37) (SEQ ID NO: 1), a second Lys residue at a position corresponding to position 37 of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of seven amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 1); which derivative comprises two protractors attached to said first and second Lys residue, respectively, each via a linker; wherein the protractor is selected from:HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;*, and&#x2003;&#x2003;Chem. 1:HOOC&#x2014;(CH)&#x2014;CO&#x2014;*,&#x2003;&#x2003;Chem. 2:wherein y is an integer in the range of 8-11, and x is 12; and the linker comprises at least one of:*&#x2014;NH&#x2014;CH(COOH)&#x2014;(CH)&#x2014;CO&#x2014;*,&#x2003;&#x2003;Chem. 3:*&#x2014;NH&#x2014;CH((CH)&#x2014;COOH)&#x2014;CO&#x2014;*, and/or&#x2003;&#x2003;Chem. 4:*&#x2014;NH&#x2014;(CH)&#x2014;[O&#x2014;(CH)]&#x2014;O&#x2014;[CH]&#x2014;CO&#x2014;*,&#x2003;&#x2003;Chem. 5:wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical uses thereof, such as for the treatment of diabetes and obesity, as well as to the GLP-1 peptides forming part of these derivatives which have Lys residues at positions 36 and 37 and no other Lys residues, and the GLP-1(9-37) fragments thereof. The invention furthermore relates to an intermediate product comprising 3-carboxyphenoxy-nonanoic acid with a protection group at the carboxy group of the nonanoic acid, optionally via a linker. The derivatives have a very good potency and a long half-life which makes them potentially useful for, e.g., oral administration.

Double-acylated GLP-1 compounds

The invention relates to a derivative of a GLP-1 analog of a general Formula I, which derivative comprises a side chain attached to a Lys residue at position 34, 35, 36, 37, 38, or 39 of the GLP-1 analog. The side chain comprises a Branched linker, a 1and a 2Protractor and a Pre-linker. The Branched linker is connected to the Lys residue of the GLP-1 analog via the Pre-linker and to the 1and the 2Protractor via a 1and 2Post-linker, respectively. The Branched linker may, e.g., be a tri-radical of Lys. The 1and the 2Protractor is C20 diacid. Various linker elements may be used in the Prelinker as well as the two Post-linkers. The invention also relates to novel GLP-analogs, novel side chain intermediates and their manufacture and use to prepare derivatives of biologically active peptides and proteins, as well as pharmaceutical compositions and medical uses of the analogs and derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

The invention relates to a derivative of a GLP-1 peptide, which peptide has two Lys residues, namely a first and a second Lys residue, and a maximum of eight amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3), which derivative comprises two protracting moieties attached to the epsilon amino group of said first and second Lys residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 15: HOOC&#x2014;(CH)&#x2014;CO&#x2014;*, and Chem. 16: HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;*, in which x is an integer in the range of 10-16, and y is an integer in the range of 8-12; and the linker comprises a first linker element *&#x2014;NH&#x2014;CH(CHOH)&#x2014;CO&#x2014;*. A preferred linker is gGlu-Ser-Ser-Gly-Ser-Ser-Gly (SEQ ID NO: 2). The derivative of the invention has a very good potency, and a very good binding to the GLP-1 receptor. The invention also relates to the pharmaceutical use of the derivative, for example in the treatment and/or prevention of all forms of diabetes and related diseases.

GLP-1 derivatives

The present invention relates to tri-acylated GLP-1 derivatives, acylated at positions corresponding to positions (18, 22, 30), (18, 26, 37), (18, 27, 37), (26, 30, 37), or (27, 30, 37) of the native human glucagon-like peptide 1 (GLP-1 (7-37) (SEQ ID NO: 1); or pharmaceutically acceptable salts, amides, or esters thereof. The acylated side chains comprise a protracting moiety selected from Chem. 1: HOOC&#x2014;(CH)&#x2014;CO&#x2014;*, Chem. 1a: HOOC&#x2014;(CH)&#x2014;CO&#x2014;*, and Chem. 2: HOS&#x2014;(CH)&#x2014;CO&#x2014;*, and the protracting moieties are connected, via a linker, to a Lys residue of the GLP-1 peptide. The GLP-1 peptide has a maximum of seven amino acid changes as compared to GLP-1 (7-37) (SEQ ID NO: 1). The invention also relates to intermediate products in the form of novel GLP-1 analogs, as well as to pharmaceutical compositions and uses of the derivatives and analogs, in particular for the treatment of type 2 diabetes. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

GLP-1 derivatives, and uses thereof

The invention relates to a derivative of a GLP-1 analogue, optionally C-terminally extended, which derivative comprises a first and a second protracting moiety in the form of a C20 or C22 diacid radical, a bis-amino branched linker, and a first and a second further linker each comprising an OEG-like linker element; wherein these elements are interconnected via amide bonds and attached to a Lys residue of the GLP-1 analogue. The invention also relates to intermediate products in the form of novel GLP-1 analogues incorporated in the derivatives of the invention, as well pharmaceutical compositions and medical uses of the derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

The invention relates to derivatives of GLP-1 like peptides which are C-terminally extended analogs of native GLP-1. The derivatives comprise two side chains, one at a position corresponding to position 42, and one at a position corresponding to position 18, 23, 27, 31, 36, or 38, wherein both positions are when compared to GLP-1(7-37). The side chains comprise a C19, C20, or C22 diacid protracting moiety and optionally a linker. The invention also relates to intermediate products in the form of novel GLP-1 analogs incorporated in the derivatives of the invention, as well as pharmaceutical compositions and medical uses of the derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

Derivatives of GLP-1 like peptides, and uses thereof

The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 27 of GLP-1(7-37) (SEQ ID NO: 1); a second K residue at a position corresponding to position T of GLP-1(7-37), where T is an integer in the range of 7-37 except 18 and 27; and a maximum of ten amino acid changes as compared to GLP-1(7-37); wherein the first K residue is designated K, and the second K residue is designated K; which derivative comprises two albumin binding moieties attached to Kand K, respectively, via a linker, wherein the albumin binding moiety comprises a protracting moiety selected from HOOC&#x2014;(CH)&#x2014;CO&#x2014; and HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;; in which x is an integer in the range of 6-16, and y is an integer in the range of 3-17; wherein the linker comprises an element of the formula &#x2014;NH&#x2014;(CH)&#x2014;(O&#x2014;(CH))&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel GLP-1 analogs. The derivatives are suitable for oral administration.

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Vaerloese, Denmark

Jacob Kofoed