Novo Nordisk A/s

Novo Nordisk Healthcare Ag

Lau, Jesper

Patrick William Garibay

Jesper F Lau

Janos Tibor Kodra

Jacob Kofoed

Thomas Hoeg-Jensen

Peter Madsen

Lars Linderoth

Jane Spetzler

Palle Jakobsen

Thomas Kruse

Ib Jonassen

Tina Moeller Tagmose

Henning Thoegersen

Lauge Schaeffer

Paw Bloch

Steffen Reedtz-Runge

Tina Møller Tagmose

Ingrid Pettersson

Thomas Boerglum Kjeldsen

Birgit Wieczorek

Per Sauerberg

Svend Havelund

Carsten Behrens

Thomas Børglum Kjeldsen

Henning Thøgersen

Henrik Sune Andersen

Bernd Peschke

Kjeld Madsen

Nils Langeland Johansen

Frantisek Hubalek

Flemming Seier Nielsen

Asser Sloth Andersen

Peter Kresten Nielsen

Jianhe Chen

Claus Ulrich Jessen

Soeren Oestergaard

Kilian Waldemar Conde Frieboes

János Tibor Kodra

Tine Glendorf

Jacob Sten Petersen

Jens Christian Norrild

Birgitte Nissen

Inga Sig Nielsen Nørby

Xujia Zhang

Caspar Christensen

Birgitte Andersen

Soren Erik Bjorn

Niels Kristian Klausen

Lauge Schäffer

Dorte Xenia Gram

Alice Ravn Madsen

Charlotte Harkjaer Fynbo

Rita Slaaby

Søren Østergaard

Thomas Høeg-Jensen

Sonja Bak

Christoph Kalthoff

Jaanos Tibor Kodra

Helle Fabricius Woeldike

Kristian Sass Bak-Jensen

Salka Elboel Rasmussen

Jesper Færgeman Lau

Bírgítte Andersen

Henning THØGERSEN

Sören Bjorn

Thomas Berglum Kjeldsen

Charlotte Harkjær Fynbo

Steffen Runge

Helle WÖLDIKE

Inga Sig Nielsen NØRBY

Salka Elbøl Rasmussen

Jishu Wang

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 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 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 solid pharmaceutical compositions for oral administration comprising a GLP-1 agonist, an absorption enhancer which is a salt of medium-chain fatty acid, and an enteric coating as well as uses thereof.

Tablets comprising GLP-1 agonist and enteric coating

Novel acylated insulin analogues exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analogues contain B25H and A14E or A14H.

Protease stabilized acylated insulin analogues

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;(CH2)x-CO&#x2014;*, and Chem. 16: HOOC&#x2014;C6H4-O&#x2014;(CH2)y-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(CH2OH)&#x2014;CO&#x2014;*. A preferred linker is g Glu-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.

A semi-recombinant method for the production of GLP-1 analogues and derivatives with non-proteogenic amino acids in the N-terminal part combining the use of recombinant expression techniques and chemical peptide synthesis.

Semi-recombinant preparation of GLP-1 analogues

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.

Analogs of FGF21 carrying a modifying, substituted ethylene or benzyl group can be used for treatment or prevention of diabetes, dyslipidemia, obesity, cardiovascular diseases, metabolic syndrome, and/or Non Alcoholic Fatty Liver Disease (NAFLD).

N-terminal modified FGF21 compounds

The invention relates to truncated GLP-1 analogs, in particular a GLP-1 analog which is a modified GLP-1(7-35) (SEQ ID No 1) having: i) a total of 2, 3, 4, 5 6, 7, 8, or 9 amino acid substitutions as compared to GLP-1(7-35), including a) a Glu residue at a position equivalent to position 22 of GLP-1(7-35), and b) an Arg residue at a position equivalent to position 26 of GLP-1(7-35); as well as derivatives thereof, and therapeutic uses and compositions. These analogs and derivatives are highly potent, have a good binding affinity to the GLP-1 receptor, also to the extracellular domain of the GLP-1 receptor, which is of potential relevance achieving long-acting, stable GLP-1 compounds with a potential for once weekly administration.

Truncated GLP-1 derivatives and their therapeutical use

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Holte, Denmark

Patrick William Garibay