Novo Nordisk A/s

Novo Nordick A/s

Transtech Pharma, Inc.

Lau, Jesper

Paw Bloch

Jesper F Lau

Janos Tibor Kodra

Lone Jeppesen

Robert Carl Andrews

Dharma Rao Polisetti

Mustafa Guzel

Michael Ankersen

Anthony Murray

Govindan Subramanian

Per Vedso

Adnan M M Mjalli

Patrick William Garibay

Kalpathy Chidambareswaran Santhosh

Thomas Kruse Hansen

Jacob Kofoed

Niels Blume

Maria Carmen Valcarce Lopez

Peter Madsen

Thomas Kruse

Carsten Behrens

Kjeld Madsen

Lars Linderoth

Inge Thoger Christensen

Asser Sloth Andersen

Claus Ulrich Jessen

Florencio Zaragoza Dörwald

Jens Christian Norrild

János Tibor Kodra

Maria Carmen Valcarce-Lopez

Lotte Bjerre Knudsen

Inga Sig Nielsen Nørby

Caspar Christensen

Adnan Mm Mjalli

Michael Paolo Bastner Sandrini

Florencio Zaragoza Doerwald

Santhosh Chidambareswaran Kalpathy

Jim McGuire

Anna Secher

Adam Paul Chambers

Nikolaj Kulahin Roed

Poul Enrico Nielsen

Jesper Færgeman Lau

Jim Mcguire

Inga Sig Nielsen NØRBY

Henrik Stephensen

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.

Compounds for treatment of obesity

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 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

This invention relates to aryl carbonyl derivatives which are activators of glucokinase which may be useful for the management, treatment, control, or adjunct treatment of diseases, where increasing glucokinase activity is beneficial.

Aryl carbonyl derivatives as therapeutic agents

Protracted GLP-1 compounds and therapeutic uses thereof.

Acylated GLP-1 compounds

Novel compounds that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.

Glucagon antagonists/inverse agonists

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Taastrup, Denmark

Paw Bloch