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    Double-acylated GLP-1 compounds
    1.
    发明授权
    Double-acylated GLP-1 compounds 有权

    公开(公告)号：US10689429B2

    公开(公告)日：2020-06-23

    申请号：US15301960

    申请日：2015-04-07

    Applicant: Novo Nordisk A/S

    Inventor： Lars Linderoth ,  Jacob Kofoed ,  Jesper Lau ,  Paw Bloch ,  Patrick William Garibay ,  Janos Tibor Kodra

    IPC: C07K14/605 ,  C07C235/20 ,  A61K38/00

    Abstract: 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—C6H4—O—(CH2)y—CO—*, and  Chem. 1: HOOC—(CH2)x—CO—*,  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: *—NH—CH(COOH)—(CH2)2—CO—*,  Chem. 3: *—NH—CH((CH2)2—COOH)—CO—*, and/or  Chem. 4: *—NH—(CH2)2—[O—(CH2)2]k—O—[CH2]n—CO—*,  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 derivatives
    2.
    发明授权
    Double-acylated GLP-1 derivatives 有权

    公开(公告)号：US10604554B2

    公开(公告)日：2020-03-31

    申请号：US15966642

    申请日：2018-04-30

    Applicant: Novo Nordisk A/S

    Inventor： Jacob Kofoed ,  Patrick William Garibay ,  Jesper Lau

    IPC: C07K14/605 ,  A61K38/26 ,  A61K38/00

    Abstract: 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—(CH2)x—CO—*, and Chem. 2: HOOC—C6H4—O—(CH2)y—CO—*, 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: *—NH—(CH2)q—CH[(CH2)w—NR1R2]—CO—*, which is connected at its CO—* 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, R1 and R2 independently represent *—H or *—CH3, 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.

    GLP-1 derivatives
    3.
    发明授权
    GLP-1 derivatives 有权

    公开(公告)号：US10308700B2

    公开(公告)日：2019-06-04

    申请号：US15404808

    申请日：2017-01-12

    Applicant: Novo Nordisk A/S

    Inventor： Jesper Lau ,  Paw Bloch ,  Jacob Kofoed ,  Patrick William Garibay

    IPC: A61K38/00 ,  A61K38/26 ,  C07K14/605

    Abstract: 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—(CH2)x—CO—*, and Chem. 16: HOOC—C6H4—O—(CH2)y—CO—*, 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 *—NH—CH(CH2OH)—CO—*. 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.

    Double-Acylated GLP-1 Derivatives
    4.
    发明申请
    Double-Acylated GLP-1 Derivatives 审中-公开

    公开(公告)号：US20180244742A1

    公开(公告)日：2018-08-30

    申请号：US15966642

    申请日：2018-04-30

    Applicant: Novo Nordisk A/S

    Inventor： Jacob Kofoed ,  Patrick William Garibay ,  Jesper Lau

    IPC: C07K14/605 ,  A61K38/26 ,  A61K38/00

    CPC classification number: C07K14/605 ,  A61K38/00 ,  A61K38/26

    Abstract: 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—(CH2)x—CO-*, and Chem. 2: HOOC—C6H4—O—(CH2)y—CO-*, 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: *—NH—(CH2)q—CH[(CH2)w—NR1R2]—CO-*, which is connected at its CO-* 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, R1 and R2 independently represent *—H or *—CH3, 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.

    NOVEL GLP-1 RECEPTOR AGONISTS WITH CHOLESTEROL EFFLUX ACTIVITY
    8.
    发明申请
    NOVEL GLP-1 RECEPTOR AGONISTS WITH CHOLESTEROL EFFLUX ACTIVITY 审中-公开
    新型GLP-1受体激动剂与胆固醇激素活性

    公开(公告)号：US20150344540A1

    公开(公告)日：2015-12-03

    申请号：US14653976

    申请日：2013-12-19

    Applicant: NOVO NORDISK A/S

    Inventor： Christian Wenzel Tornoee ,  Henning Thoegersen ,  Bidda Charlotte Rolin ,  Janos Tibor Kodra ,  Salka Elboel Rasmussen ,  Jesper Lau

    IPC: C07K14/605

    CPC classification number: C07K14/605

    Abstract: The present invention provides novel glucagon-like protein-1 (GLP-1) receptor agonist compounds that promote cholesterol efflux. The ABCA1-mediated cholesterol efflux present invention also provides compositions comprising the novel glucagon-like protein-1(GLP-1) receptor agonist compounds, and relates to the use of said compounds in therapy, to methods of treatment comprising administration of said compounds to patients, and to the use of said compounds in the manufacture of medicaments.

    Abstract translation: 本发明提供促进胆固醇流出的新型胰高血糖素样蛋白-1（GLP-1）受体激动剂化合物。 ABCA1介导的胆固醇流出本发明还提供了包含新型胰高血糖素样蛋白-1（GLP-1）受体激动剂化合物的组合物，并且涉及所述化合物在治疗中的用途，包括给予所述化合物至 患者以及所述化合物在制备药物中的用途。

    Truncated GLP-1 Derivatives and Their Therapeutical Use
    9.
    发明申请
    Truncated GLP-1 Derivatives and Their Therapeutical Use 审中-公开
    截短的GLP-1衍生物及其治疗用途

    公开(公告)号：US20140296131A1

    公开(公告)日：2014-10-02

    申请号：US14299638

    申请日：2014-06-09

    Applicant: Novo Nordisk A/S

    Inventor： Jane Spetzler ,  Lauge Schaeffer ,  Jesper Lau ,  Janos T. Kodra ,  Kjeld Madsen ,  Patrick W. Garibay ,  Jacob Kofoed ,  Steffen Reedtz-Runge ,  Henning Thoegersen ,  Ingrid Pettersson

    IPC: C07K14/605

    CPC classification number: C07K14/605 ,  A61K38/00

    Abstract: The invention relates to truncated GLP-1 analogues, in particular a GLP-1 analogue 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 analogues 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.

    Abstract translation: 本发明涉及截短的GLP-1类似物，特别是GLP-1类似物，其是修饰的GLP-1（7-35）（SEQ ID No.1），其具有：i）总共2,3,4,5,6 ，7,8或9个氨基酸取代，其包括a）在等同于GLP-1（7-35）的位置22的位置上的Glu残基，和b）Arg 在等同于GLP-1（7-35）的第26位的位置上的残基; 以及其衍生物，以及治疗用途和组合物。 这些类似物和衍生物是高度有效的，对GLP-1受体以及GLP-1受体的细胞外结构域具有良好的结合亲和力，这与具有潜在的长效，稳定的GLP-1化合物具有潜在的相关性 每周一次行政。

    Compounds for treatment of obesity
    10.
    发明授权
    Compounds for treatment of obesity 有权

    公开(公告)号：US11753455B2

    公开(公告)日：2023-09-12

    申请号：US17253708

    申请日：2019-06-20

    Applicant: Novo Nordisk A/S

    Inventor： Nikolaj Kulahin Roed ,  Michael Paolo Bastner Sandrini ,  Jesper Lau ,  Paw Bloch ,  Anna Secher ,  Adam Paul Chambers ,  Jim McGuire ,  Lotte Bjerre Knudsen

    IPC: C07K14/575 ,  A61K47/62 ,  A61K38/00

    CPC classification number: C07K14/575 ,  A61K47/62 ,  A61K38/00 ,  C07K2319/74

    Abstract: The invention relates to a construct comprising a compound targeting areas in the brain involved in the regulation of body weight and an allosteric ligand to a receptor located in the blood-brain barrier (BBB). The invention also relates to compositions and uses of such construct, for example in the prevention or treatment of overweight and obesity. Preferred compounds for regulation of body weight include GLP-1 receptor agonists (GLP-1RA), and preferred receptors located in the BBB include the transferrin receptor (TfR). Exemplary fusions and conjugates of GLP-1 RA's and anti TfR-Fab's exhibit an increased binding to brain regions expressing the GLP-1 receptor as compared to fusions or conjugates with inactive control Fab's, in particular in brain areas protected by the BBB. In vivo mice studies confirm increased reduction in food intake as well as weight loss for the active construct compared to the inactive one.

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