Exendin-4 derivatives as dual glp1/glucagon agonists

Abstract

The present invention relates to exendin-4 derivatives and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as reduction of excess food intake.

1 - 31 . (canceled) 
     
     
         32 . A method of treating or preventing of diseases or disorders caused by, associated with and/or accompanied by disturbances in carbohydrate and/or lipid metabolism, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a peptidic compound having formula (I):
   R 1 —Z—R 2   (I)
   or a salt, or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or salt or solvate thereof as an active agent together with at least one pharmaceutically acceptable carrier,   wherein Z is a peptide moiety having formula (II):
   His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-X16-X17-X18-Ala-X20-X21-Phe-Ile-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-X35-Pro-Pro-Pro-X39-X40  (II)
 
   wherein:   X2 is an amino acid residue selected from Ser, D-Ser, and Aib,   X3 is an amino acid residue selected from Gln, His, and α-amino-functionalized Gln, wherein Gln is optionally functionalized in that an H of the α-NH 2  group is substituted by (C 1 -C 4 )-alkyl,   X14 is an amino acid residue having a side chain with a functionalized —NH 2  group, wherein the functionalized —NH 2  side chain group is functionalized by —C(O)—R 5 , —C(O)O—R 5 , —C(O)NH—R 5 , —S(O) 2 —R 5  or R 5 , wherein R 5  is a moiety comprising up to 100 carbon atoms and optionally heteroatoms independently selected from halogen, N, O, S, P, and combinations thereof,   X15 is an amino acid residue selected from Glu and Asp,   X16 is an amino acid residue selected from Ser, Glu, and Lys,   X17 is an amino acid residue selected from Arg, Glu, Gln, Leu, Aib, and Lys,   X18 is an amino acid residue selected from Arg, Ala, and Lys,   X20 is an amino acid residue selected from Gln, Arg, Lys, His, Glu, and Aib,   X21 is an amino acid residue selected from Asp, Leu, and Glu,   X28 is an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Ala, and Asp,   X29 is an amino acid residue selected from Gly, Ala, D-Ala, and Thr,   X35 is an amino acid residue selected from Ala, Glu, Arg, and Lys,   X39 is Ser or is absent, and   X40 is absent or is an amino acid residue having a side chain with an —NH 2  group, wherein the —NH 2  side chain group is optionally functionalized by —C(O)—R 5 , —C(O)O—R 5 , —C(O)NH—R 5 , —S(O) 2 —R 5  or R 5 , wherein R 5  is a moiety comprising up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S, P, and combinations thereof,   R 1  is the N-terminal group of the peptidic compound and is selected from —NH 2  and mono- or bisfunctionalized —NH 2 , wherein the mono- or bisfunctionalized —NH 2  is selected from the group consisting of —NH[(C 1 -C 5 )alkyl], —N[(C 1 -C 5 )alkyl] 2 , —NH[(C 0 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl], NH—C(O)—H, NH—C(O)—(C 1 -C 5 )-alkyl, and NH—C(O)—(C 0 -C 3 )alkylene-(C 3 -C 8 )cycloalkyl, in which alkyl or cycloalkyl is unsubstituted or up to 5-fold substituted by —OH or halogen selected from F, Cl, Br, and I,   R 2  is the C-terminal group of the peptidic compound and is selected from   (i) —OH and functionalized —OH, wherein the functionalized —OH is selected from —O—(C 1 -C 20 )alkyl and —O(C 0 -C 8 )alkylene-(C 3 -C 8 )cycloalkyl, and   (ii) —NH 2  and mono- or bisfunctionalized —NH 2 , wherein the mono- or bisfunctionalized —NH 2  is selected from the group consisting of —NH[(C 1 -C 30 )alkyl], —N[(C 1 -C 30 )alkyl] 2 , —NH[(C 0 -C 8 )alkylene-(C 3 -C 8 )cycloalkyl], —N[C 0 -C 8 )alkylene-(C 3 -C 8 )cycloalkyl] 2 , —NH[(CH 2 —CH 2 —O) 1-40 —(C 1 -C 4 )alkyl], —NH—(C 3 -C 8 )heterocyclyl or —NH—(C 0 -C 8 )alkylene-aryl, wherein aryl is selected from phenyl or naphthyl, the (C 3 -C 8 )-heterocyclyl contains one N-atom and optionally two additional heteroatoms selected from O, N and S, and alkyl or cycloalkyl is unsubstituted or up to 5-fold substituted by —OH or a halogen selected from F, Cl, Br, and I.   
     
     
         33 . The method according to  claim 32 , wherein said method comprises delaying or preventing disease progression in type 2 diabetes, treating metabolic syndrome, treating obesity or preventing overweight, decreasing food intake, increasing energy expenditure, reducing body weight, delaying the progression from impaired glucose tolerance (IGT) to type 2 diabetes; delaying the progression from type 2 diabetes to insulin-requiring diabetes; regulating appetite; inducing satiety; preventing weight regain after successful weight loss; treating a disease or state related to overweight or obesity; treating bulimia; treating binge eating; treating atherosclerosis, hypertension, IGT, dyslipidemia, coronary heart disease, hepatic steatosis, treatment of beta-blocker poisoning, inhibition of the motility of the gastro-intestinal tract, investigations of the gastro-intestinal tract using techniques such as X-ray, CT- and NMR-scanning. 
     
     
         34 . A method of treating or preventing hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, and metabolic syndrome in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the peptidic compound of formula (I) or a salt, or solvate thereof according to  claim 32 , or a pharmaceutical composition according to  claim 32 . 
     
     
         35 . The method according to  claim 34 , wherein said method comprises the treatment and/or prevention of obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, and/or obesity induced sleep apnea. 
     
     
         36 . The method according to  claim 34 , wherein said method simultaneously treats obesity and diabetes. 
     
     
         37 . A method of treating or preventing neurodegenerative disorders in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the peptidic compound of formula (I) or a salt, or solvate thereof according to  claim 32 , or a pharmaceutical composition according to  claim 32 . 
     
     
         38 . The method according to  claim 37 , wherein said neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, ataxia, e.g spinocerebellar ataxia, Kennedy disease, myotonic dystrophy, Lewy body dementia, multi-systemic atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, prion-associated diseases, e.g. Creutzfeldt-Jacob disease, multiple sclerosis, telangiectasia, Batten disease, corticobasal degeneration, subacute combined degeneration of spinal cord, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, infantile Refsum disease, Refsum disease, neuroacanthocytosis, Niemann-Pick disease, Lyme disease, Machado-Joseph disease, Sandhoff disease, Shy-Drager syndrome, wobbly hedgehog syndrome, proteopathy, cerebral β-amyloid angiopathy, retinal ganglion cell degeneration in glaucoma, synucleinopathies, tauopathies, frontotemporal lobar degeneration (FTLD), dementia, cadasil syndrome, hereditary cerebral hemorrhage with amyloidosis, Alexander disease, seipinopathies, familial amyloidotic neuropathy, senile systemic amyloidosis, serpinopathies, AL (light chain) amyloidosis (primary systemic amyloidosis), AH (heavy chain) amyloidosis, AA (secondary) amyloidosis, aortic medial amyloidosis, ApoAI amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, familial amyloidosis of the Finnish type (FAF), Lysozyme amyloidosis, Fibrinogen amyloidosis, Dialysis amyloidosis, Inclusion body myositis/myopathy, Cataracts, Retinitis pigmentosa with rhodopsin mutations, medullary thyroid carcinoma, cardiac atrial amyloidosis, pituitary prolactinoma, hereditary lattice corneal dystrophy, Cutaneous lichen amyloidosis, Mallory bodies, corneal lactoferrin amyloidosis, pulmonary alveolar proteinosis, odontogenic (Pindborg) tumor amyloid, cystic fibrosis, sickle cell disease or critical illness myopathy (CIM). 
     
     
         39 . The method according to  claim 32 , wherein said pharmaceutical composition is administered parenterally. 
     
     
         40 . The method according to  claim 39 , wherein said parenteral administration is selected from subcutaneous, intramuscular, intravenous, intradermal and transdermal administration. 
     
     
         41 . The method according to  claim 32 , wherein said pharmaceutical composition is administered in a single dose injectable form. 
     
     
         42 . The method according to  claim 41 , wherein said single dose injectable form is in the form of a pen. 
     
     
         43 . The method according to  claim 32 , wherein said compound, salt or solvate thereof of formula (I) or said pharmaceutical composition is administered in combination with at least one additional therapeutically active agent. 
     
     
         44 . The method according to  claim 43 , wherein said at least one additional therapeutically active agent is administered simultaneously, separately or sequentially with respect to the administration of the compound, salt or solvate thereof of formula (I) or the pharmaceutical composition. 
     
     
         45 . The method according to  claim 43 , wherein said pharmaceutical composition comprises the at least one additional therapeutically active agent. 
     
     
         46 . The method according to  claim 43 , wherein said at least one additional therapeutically active agent is selected from a GLP-1 compound, an insulinic compound, and a gastrointestinal peptide. 
     
     
         47 . The method according to  claim 43 , wherein said at least one additional therapeutically active agent is selected from insulin and an insulinic compound. 
     
     
         48 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X14 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2  side chain group is functionalized by —C(O)—R 5 , and   X40 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2  side chain group is optionally functionalized by —C(O)—R 5 ,   where R 5  is a lipophilic moiety selected from an acyclic (C 4 -C 30 ) hydrocarbon group which is linear, branched, saturated or unsaturated, or a cyclic hydrocarbon group which is saturated, unsaturated or aromatic, wherein the lipophilic moiety is optionally attached to the —NH 2  side chain group by a linker selected from (β-Ala) 1-4 , (γ-Glu) 1-4 , (ε-Ahx) 1-4 , or (GABA) 1-4  in all stereoisomeric forms.   
     
     
         49 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X14 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2  side chain group is functionalized by —C(O)—R 5 ,   X40 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2  side chain group is optionally functionalized by —C(O)—R 5 , and —C(O)—R 5  is selected from the group consisting of: (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, 4-Hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-, Hexadecanoyl-, (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl-, (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-propionylamino]-propionylamino}-butyryl, (S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-, (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl, (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-butyryl, (S)-4-Carboxy-4-tetradecanoylamino-butyryl-, (S)-4-(11-Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl, (S)-4-Carboxy-4-[11-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl-, (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, (S)-4-Carbo xy-4-docosanoylamino-butyryl-, (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-[(4′-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-, (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-Carboxy-4-icosanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-, 3-(3-Octadecanoylamino-propionylamino)-propionyl-, 3-(3-Hexadecanoylamino-propionylamino)-propionyl-, 3-Hexadecanoylamino-propionyl-, (S)-4-Carboxy-4-[(R)-4-((3R,5S,7R,8R,9R,10S,12S,13R,14R,17R)-3,7,12-trihydroxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-[(R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carbo xy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylamino)-butyryl-, Tetradecanoyl-, 11-Carboxy-undecanoyl-, 11-Benzyloxycarbonyl-undecanoyl, (S)-4-Carboxy-4-((S)-4-carboxy-4-tetradecanoylamino-butyrylamino)-butyryl-, 6-[Hydroxy-(naphthalen-2-yloxy)-phosphoryloxy]-hexanoyl-, 6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-, 4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-, 4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, (S)-4-Carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetyl, (S)-4-Carboxy-4-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-butyrylamino}-butyrylamino)-butyryl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-1H-tetrazol-5-yl-hexadecanoylamino)-butyrylamino]-ethoxy}- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-carboxy-hexadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-((S)-4-carboxy-4-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)-decanoylamino]-butyrylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(7-carboxy-heptanoylamino)-butyrylamino]- ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(11-carboxy-undecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(13-carboxy-tridecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-[(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino]-butyryl, and (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl.   
     
     
         50 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof, R 1  is —NH 2 , R 2  is —NH 2 , or R 1  and R 2  are —NH 2 . 
     
     
         51 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof, X14 is Lys, which is functionalized with a group —C(O)R 5 , wherein R 5  is a moiety comprising up to 100 carbon atoms and optionally heteroatoms independently selected from halogen, N, O, S, P, and combinations thereof. 
     
     
         52 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof, X14 is Lys, which is functionalized with a group —C(O)R 5 , wherein R 5  is an acyclic linear or branched (C 12 -C 22 ) saturated hydrocarbon group attached directly to the —NH 2  side chain group or attached to the —NH 2  side chain group by a linker selected form the group consisting of β-Ala, γ-Glu, β-Ala-β-Ala, and γ-Glu-γ-Glu in all stereoisomeric forms. 
     
     
         53 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X2 is an amino acid residue selected from Ser, D-Ser, and Aib,   X3 is an amino acid residue selected from Gln, His, and α-amino-functionalized Gln, wherein Gln is optionally functionalized in that an H of the α-NH 2  group is substituted by (C 1 -C 4 )-alkyl,   X14 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2  side chain group is functionalized by —C(O)—R 5 ,   X15 is an amino acid residue selected from Glu and Asp,   X16 is an amino acid residue selected from Ser, Lys, and Glu,   X17 is an amino acid residue selected from Arg, Glu, Gln, Leu, and Lys,   X18 is an amino acid residue selected from Arg and Ala,   X20 is an amino acid residue selected from Gln, Arg, Lys, and Aib,   X21 is an amino acid residue selected from Asp, Leu, and Glu,   X28 is an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Asp, and Ala,   X29 is an amino acid residue selected from Gly, Ala, D-Ala, and Thr,   X35 is an amino acid residue selected from Ala and Glu,   X39 is Ser or is absent, and   X40 is either absent or is Lys, wherein the —NH 2  side chain group is optionally functionalized by —C(O)—R 5 , wherein R 5  is a lipophilic moiety selected from an acyclic (C 4 -C 30 ) hydrocarbon group which is linear, branched, saturated or unsaturated, or a cyclic hydrocarbon group which is saturated, unsaturated or aromatic, wherein the lipophilic moiety is optionally attached to the —NH 2  side chain group by a linker selected from (β-Ala) 1-4 , (γ-Glu) 1-4 , (ε-Ahx) 1-4 , or (GABA) 1-4  in all stereoisomeric forms.   
     
     
         54 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X2 is an amino acid residue selected from D-Ser and Aib,   X3 is Gln,   X14 is an amino acid residue selected from Lys and Orn, wherein the —NH 2  side chain group is functionalized by —C(O)—R 5 ,   X15 is an amino acid residue selected from Glu and Asp,   X16 is an amino acid residue selected from Ser and Glu,   X17 is an amino acid residue selected from Arg, Gln, and Lys,   X18 is an amino acid residue selected from Arg and Ala,   X20 is an amino acid residue selected from Gln, Arg, Lys, and Aib,   X21 is an amino acid residue selected from Asp, Leu, and Glu,   X28 is an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, and Ala,   X29 is an amino acid residue selected from Gly, Ala, and Thr,   X35 is Ala,   X39 is Ser or is absent, and   X40 is either absent or is Lys, wherein the —NH 2  side chain group is optionally functionalized by —C(O)—R 5 , wherein R 5  is a lipophilic moiety selected from an acyclic (C 4 -C 30 ) hydrocarbon group which is linear, branched, saturated or unsaturated, or a cyclic hydrocarbon group which is saturated, unsaturated or aromatic, wherein the lipophilic moiety is optionally attached to the —NH 2  side chain group by a linker selected from (β-Ala) 1-4 , (γ-Glu) 1-4 , (ε-Ahx) 1-4 , or (GABA) 1-4  in all stereoisomeric forms.   
     
     
         55 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X20 is an amino acid residue selected from Gln, Lys, and Aib.   
     
     
         56 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X2 is an amino acid residue selected from D-Ser or Aib,   X3 is Gln,   X14 is Lys, wherein the —NH 2  side chain group is functionalized by one of the groups selected from the group consisting of 3-(3-octadecanoylamino-propionyl-amino)-propionyl-, 4-hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, hexadecanoyl-, (S)-4-carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-carboxy-4-henicosanoylamino-butyryl-, (S)-4-carboxy-4-docosanoylamino-butyryl-, (S)-4-carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-carboxy-4-1(4′-octyloxy-biphenyl-4-carbonyl)-aminol-butyryl-, (S)-4-carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-, (S)-4-carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4-carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-, (S)-4-carboxy-4-octadecanoylamino-butyryl-, or (S)-4-carboxy-4-hexadecanoylamino-butyryl-,   X15 is Glu,   X16 is Ser,   X17 is an amino acid residue selected from Arg, Gln, and Lys,   X18 is Ala,   X20 is Gln,   X21 is Asp,   X28 is Ala,   X29 is Gly,   X35 is Ala,   X39 is Ser, and   X40 is absent.   
     
     
         57 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X2 is Aib,   X3 is Gln,   X14 is Lys, wherein the —NH 2  side chain group is optionally functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl- or (S)-4-Carboxy-4-octadecanoylamino-butyryl-,   X15 is an amino acid residue selected from Asp and Glu,   X16 is an amino acid residue selected from Ser and Glu,   X17 is an amino acid residue selected from Gln and Lys,   X18 is Ala,   X20 is an amino acid residue selected from Gln and Lys,   X21 is an amino acid residue selected from Asp and Leu,   X28 is Ala,   X29 is an amino acid residue selected from Gly and D-Ala,   X35 is Ala,   X39 is Ser, and   X40 is absent.   
     
     
         58 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X2 is D-Ser,   X3 is Gln,   X14 is Lys, wherein the —NH 2  side chain group is optionally functionalized by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-,   X15 is an amino acid residue selected from Glu and Asp,   X16 is an amino acid residue selected from Ser and Glu,   X17 is an amino acid residue selected from Arg, Glu, Lys, and Aib,   X18 is an amino acid residue selected from Arg, Lys, and Ala,   X20 is an amino acid residue selected from Gln, Lys, and Aib,   X21 is an amino acid residue selected from Asp and Leu,   X28 is an amino acid residue selected from Ala and Asn,   X29 is Gly,   X35 is Ala,   X39 is Ser, and   X40 is absent.   
     
     
         59 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X2 is an amino acid residue selected from Aib and D-Ser;   X3 is an amino acid residue selected from Gln and His;   X14 is Lys, wherein the —NH 2  side chain group is functionalized by one of the groups selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-, 3-(3-Octadecanoylamino-propionylamino)-propionyl-, 3-(3-Hexadecanoylamino-propionylamino)-propionyl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, 4-Hexadecanoylamino-butyryl-, and 4-octadecanoylamino-butyryl-,   X15 is an amino acid residue selected from Asp and Glu;   X16 is an amino acid residue selected from Ser and Glu;   X17 is an amino acid residue selected from Arg, Gln, Lys, Aib, and Leu;   X18 is an amino acid residue selected from Arg and Ala;   X20 is an amino acid residue selected from Gln, Aib, and Lys;   X21 is an amino acid residue selected from Asp, Glu, and Lys;   X28 is an amino acid residue selected from Asn, Ser, Aib, Ala, and Arg;   X29 is an amino acid residue selected from Gly, Thr, Ala, and D-Ala;   X35 is Ala;   X39 is Ser; and   X40 is absent.   
     
     
         60 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X14 is functionalized Lys which is functionalized at its ε-amino group with —C(O)—R 5 , wherein —C(O)—R 5  is (S)-4-carboxy-4-hexadecanoylamino-butyryl, (S)-4-carboxy-4-octadecanoylamino-butyryl, hexadecanoyl, or octadecanoyl.   
     
     
         61 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X2 is an amino acid residue selected from Aib and D-Ser;   X3 is Gln;   X14 is Lys, wherein the —NH 2  side chain group is functionalized by one of the groups selected from the group consisting of (S)-4-carboxy-4-hexadecanoyl-amino-butyryl, (S)-4-carboxy-4-octadecanoylamino-butyryl, hexadecanoyl, and octadecanoyl;   X15 is Glu;   X16 is Ser;   X17 is an amino acid residue selected from Arg, Gln, and Lys;   X18 is Ala;   X20 is Gln;   X21 is Asp;   X28 is Ala;   X29 is Gly;   X35 is Ala;   X39 is Ser; and   X40 is absent.   
     
     
         62 . The method according to  claim 32 , wherein, in said peptidic compound of formula (I) or salt or solvate thereof,
 X2 is Aib,   X3 is Gln,   X14 is Lys, wherein the —NH 2  side chain group is optionally functionalized by (S)-4-Carboxy-4-henicosanoylamino-butyryl- or (S)-4-Carboxy-4-octadecanoylamino-butyryl-,   X15 is Asp,   X16 is an amino acid residue selected from Lys and Glu,   X17 is an amino acid residue selected from Arg and Glu,   X18 is an amino acid residue selected from Ala and Arg,   X20 is an amino acid residue selected from Gln and Lys,   X21 is an amino acid residue selected from Asp and Leu,   X28 is Ala,   X29 is an amino acid residue selected from Gly and D-Ala,   X35 is Ala,   X39 is Ser, and   X40 is absent.   
     
     
         63 . The method according to  claim 32 , wherein said peptidic compound of formula (I) is any one of SEQ ID NO. 4-181, or a salt or solvate thereof. 
     
     
         64 . The method according to  claim 32 , wherein said peptidic compound of formula (I) is any one of SEQ ID NO. 4-181, 196-223, 226-229, or a salt or solvate thereof. 
     
     
         65 . The method according to  claim 32 , wherein said peptidic compound of formula (I) is the amino acid sequence of SEQ ID NO.: 24, or a salt, or solvate thereof. 
     
     
         66 . The method according to  claim 32 , wherein said peptidic compound of formula (I) is the amino acid sequence of SEQ ID NO.: 35, or a salt, or solvate thereof. 
     
     
         67 . The method according to  claim 32 , wherein said peptidic compound of formula (I) is the amino acid sequence of SEQ ID NO.: 36, or a salt, or solvate thereof. 
     
     
         68 . The method according to  claim 32 , wherein said peptidic compound of formula (I) is the amino acid sequence of SEQ ID NO.: 44, or a salt, or solvate thereof. 
     
     
         69 . The method according to  claim 32 , wherein said peptidic compound of formula (I) is the amino acid sequence of SEQ ID NO.: 97, or a salt, or solvate thereof. 
     
     
         70 . The method according to  claim 32 , wherein said peptidic compound of formula (I) or salt or solvate thereof has a high solubility at at least one pH value selected from an acidic pH value and a physiological pH value, and wherein the solubility at said at least one pH value is at least 0.5 mg/ml.