Novo Nordisk A/s

Lars Linderoth

Jacob Kofoed

Patrick William Garibay

Jesper F Lau

Jane Spetzler

Thomas Kruse

Birgit Wieczorek

Janos Tibor Kodra

Per Sauerberg

Henning Thoegersen

Lauge Schaeffer

Paw Bloch

Jianhe Chen

János Tibor Kodra

Alice Ravn Madsen

Salka Elboel Rasmussen

Christoph Kalthoff

Henning THØGERSEN

Salka Elbøl Rasmussen

Birgit Wiezorek

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.

Double-acylated GLP-1 derivatives

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.

GLP-1 derivatives and uses thereof

The invention relates to compounds derived from the EGF(A) domain of LDL-R, in particular compounds comprising a peptide analogue of the wild-type EGF(A) (LDL-R(293-332)) sequence and at least one substituent comprising at least one fatty acid group. The invention also relates to a pharmaceutical composition thereof and use a medicament. The novel EGF(A) compounds of the invention are useful as treatment e.g. in the field of cholesterol lowering, dyslipidaemia and cardiovascular disease.

EGF(A) analogues with fatty acid substituents

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, 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.

The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve 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, Chem. 2, and Chem. 3:HOOC&#x2014;(CH)&#x2014;CO&#x2014;*&#x2003;&#x2003;Chem. 1:HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;*&#x2003;&#x2003;Chem. 2:R&#x2014;CH&#x2014;(CH)&#x2014;CO&#x2014;*,&#x2003;&#x2003;Chem. 3: 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 peptides and side chain intermediates. The derivatives are 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 37 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1(7-37), and a maximum of ten amino acid modifications 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, wherein the albumin binding moiety comprises a protracting moiety selected from: Chem. 1, Chem. 2, Chem. 3 or Chem. 4; or a pharmaceutically acceptable salt, amide, or ester 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 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve 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--(CH)&#x2014;CO&#x2014;*, in which x is an integer in the range of 6-18, and y is an integer in the range of 3-17; and the linker comprises Chem. 3: *&#x2014;NH&#x2014;(CH)&#x2014;CH[(CH)&#x2014;NH]&#x2014;CO&#x2014;*, wherein q is an integer in the range of 0-5, 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 peptides and side chain intermediates. The derivatives are potent, protracted, and suitable for oral administration.

Double-acylated GLP-1 derivatives with a linker

The invention relates to a GLP-1 analog which comprises a histidine (H) residue at a position corresponding to position 31 of GLP-1(7-37) (SEQ ID NO: 1), a glutamine (Q) residue at a position corresponding to position 34 of GLP-1 (7-37) (SEQ ID NO: 1), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37) (SEQ ID NO: 1); wherein the H residue is designated H, and the Q residue is designated Q; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to derivatives thereof, as well as the pharmaceutical use of these analogs and derivatives, for example in the treatment and/or prevention of all forms of diabetes and related diseases. The invention furthermore relates to corresponding novel side chain intermediates. The derivatives are suitable for oral administration.

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Alleroed, Denmark

Lars Linderoth