CA2606894A1

CA2606894A1 - Novel compounds as glp-i agonists

Info

Publication number: CA2606894A1
Application number: CA002606894A
Authority: CA
Inventors: Braj Bhushan Lohray; Vidya Bhushan Lohray; Rajesh H. Bahekar
Original assignee: Individual
Current assignee: Zydus Lifesciences Ltd
Priority date: 2005-05-05
Filing date: 2006-05-04
Publication date: 2007-02-15
Also published as: EP1891106A2; MX2007013655A; JP2008540402A; AP2007004227A0; WO2007017892A2; EA200702419A1; IL187105A0; KR20080021636A; WO2007017892A3; NO20075618L; BRPI0612471A2; AU2006277557A1

Abstract

The present invention describes a group of novel peptidomimetics useful for the treatment of diabetes. These compounds are defined by the general formula (I) as given below. A-X1- S1-Y-S2-X2-B (I)

Description

DEMANDE OU BREVET VOLUMINEUX

LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS

THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

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NOTE POUR LE TOME / VOLUME NOTE:

Field of Invention The present invention relates to novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts and pharmaceutical compositions containing them.

A-XI- Si-Y-Sa-X2-B (I) In particular, the present invention relates to novel Glucagon-Like Peptide-1 (GLP-1) peptide mimics (peptidomimetic), which act as GLP-1 receptor agonists and exhibit most of the biological activity of the native GLP-1. Furthermore, these GLP-1 peptidomimetics exhibit increased stability to proteolytic cleavage, especially against DPP-IV (Dipeptidyl peptidase-IV) enzyme and can be delivered by both invasive and various non-invasive routes of administrations such as oral, nasal, buccal, pulmonary and transdermal route of administration, for the treatment or prevention of diabetes and related conditions.
The present invention also relates to a process of preparing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and novel intermediates involved in their synthesis.
Background to the invention The GLP-1 (7-36) amide is a product of the preproglucagoin gene, which is secreted from intestinal L-cells, in response to the ingestion of food. The physiological action of GLP-1 has gained considerable interest. GLP-1 exerts multiple action by stimulating insulin secretion from pancreatic (3-cells, in a glucose dependent maiuier (insulinotropic action). GLP-1 also lowers circulating plasma glucagon concentration, by ii-Aiibiting its secretion fi-om cc-cells (Drucker D. J,, Endocrinology, 142, 521-527, 2001). More recently, it has become clear that GLP-1 also exhibits properties like stimulation of 0-cell growth, appetite suppression, delayed gastric emptying and stimulation of insulin sensitivity (Nauck, Horm. Metab. Res., 47, 1253-1258, 1997).
The venom of the Gila Monster Heloderma Suspectum contains a 39 amino acid peptide called Exendin44 (EX-4) that shares around 50 % sequence identity to itself, exhibits a very potent GLP-1R (Glucagon like peptide-1 receptor) agonist activity (Thorens B., Diabetes, 42, 1678 - 1682, 1993). Indeed, it was found that EX-4 is much more potent than native GLP-1 peptide, because of its relatively longer half-life (25 min., iv route of administration), compared to GLP-1 (2-5 min., iv route of administration). Exendin-4 binds with greater affinity to the GLP-1R, due to presence of the nine extra C-terminal sequence (Doyle M.E., Regulatory Peptides, 114, 153-158, 2003). Thus, the above stated pharniacological properties of GLP-IR agonists make it a highly desirable therapeutic agent for the treatment of diabetes.
Native or synthetic GLP-1 peptide is rapidly metabolized by the proteolytic enzymes, such as dipeptidyl peptidase-IV (DPP-IV) into an inactive metabolite, thereby limiting the use of GLP-1 as a drug. Currently, various analogs of GLP-1 and EX-4, such as Liraglutide / NN2211 (Novo Nordisk; Phase-III; WO 1998 008871), BIM
51077 (Ipsen; Phase-II; WO 2000 034331), CJC-1131 (ConjuChem; Phase-II; WO
2000 069911), ZP-10 (Zealand & Aventis; Phase-II; WO 2001 004156) are in different stages of clinical development (Nauck M.A., Regulatory Peptides, 115, 13-19, 2004).
However, all these peptides require delivery via parenteral route of administration, including BYETTA (Exendin-4, AC 2933; WO 2001 051078), which is recently launched in the market (Amylin & Lilly). Thus, there exists a critical need to develop a biologically active GLP-1 mimic that possesses extended pharmacodynamic profiles.
The GLP-1 R is a seven-transmembrane domain G-protein-coupled receptor (GPCR) and it is located on the cell membrane of pancreatic (3-cells. The effector system of GLP- 1. R is the Adenylyl Cyclase (AC) enzyme. Interaction of GLP-1 agonist with GLP-IR causes activation of AC, which converts ATP to cAMP. Increase in the intracellular cAMP level raises the ratio of ADP/ATP, thereby initiating the cell depolarization (due to closure of KATP channel). Increase in the intracellular cAMP
level also activates Protein Kinase (PK-A & PK-C), which raises the cystolic Ca2+
concentration, by opening of L-type of Ca2+ channel. An increase in the intracellular C2+ leads to exocytosis of insulin, in pancreatic 0-cells (Fehmann, H.C., Endocr. Rev., 16,390 - 410, 1995).
A general mechanism of peptide ligand interaction with class-B GPCRs has emerged recently, termed the 'two-domain' model (Hoare S.R.J., Drug Discovery Today, Vol. 10 (6), 417-427, 2005). In this two-domain model, the C-terminal portion of the peptide binds to the N-domain of the receptor and the N-terminal ligand region binds to the J-domain (transmembrane) region of GPCR. This interaction activates the receptor and thereby stimulates intracellular signaling. The receptor binding and activation occurs in two separate domains of Exendin, but they are closely coupled in GLP-1 (Eng J., J.B.C., 272 (34), 21291-21296, 1997).

Prior art Earlier, Bristol-Myers Squibb (BMS), Princeton, NJ (US), reported human GLP-1 mimics, with general formula Xaal-Xaal1, wherein Xaal-Xaa9 represent the first 1-9 residues of GLP-1 peptide with some analogs wherein Xaa2 represents either Ala or is optionally replaced with Aib, and Xaa6 represents Phe or is optionally replaced with a-Me-Phe(2-F)-OH and XaalO & Xaall represents combination of substituted or unsubstituted biphenyl alanine (Bip) derivatives (WO 03/
033671A2; US
2004/ 0127423 Al; WO 2004/ 094461 A2; US 2006 / 0004222 Al and WO 2006/
014287 Al).
The present invention provides novel GLP-1 peptide mimics of formula (I) (hereinafter referred to as peptidomimetics), which act as a GLP-IR agonist and exhibit most of the biological activity of the native GLP-1 peptide. Furthermore, these GLP-1 peptidomimetics exhibit increased stability to proteolytic cleavage, especially against DPP-IV enzyme and therefore, surprisingly found to have an increased half-life making them suitable for the treatment / mitigation / prophylaxis of both type 1&
type 2 diabetes, metabolic disorders, obesity and related disorders.
Summary of the-invention The present invention describes a group of novel peptidomimetics useful for the treatment of diabetes. These compounds are defined by the general formula (I) as given below. The compounds of the present invention are useful in the treatment of the human or animal body, by regulation of insulin secretion. The compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of both type 1 & type 2 diabetes and obesity.

Preferred embodiments The main object of the present invention is to provide novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures, suitable for the treatment treatment/mitigation/regulation of diabetes.
In an embodiment is provided a process for the preparation of novel compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.

In another embodiment, is provided pharmaceutical compositions containing compounds of general formula (I),' their tautomeric forms, their pharnlaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.
In a further another embodiment is provided the use of the novel compounds of the present invention as antidiabetic agents, by administering a therapeutically effective &
non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals those are need of such treatment.
Abbreviations used The following abbreviations are employed in the examples and elsewhere herein:
Aib = a-Aminoisobutyric acid, ACN or MeCN = Acetonitrile, Bip = Biphenylalanine residue, Bip(4-fluro)= 4-fluoro-biphenylalanine residue, Bip(2-Me)= 2-methyl biphenyl residue, Bip(2-Et)= 2-ethyl biphenyl residue, Bip(2-CN)= 2-nitrile biphenyl residue, Bip(2-Ipr)= 2-Isopropyl biphenyl residue, Bip(2'-Et-4'-OMe)= 2-ethyl-4-methoxy-biphenyl residue, Bip(2-F)= 2-fluro-biphenyl residue, Bn = Benzyl, 13oc = tert-13utoxycarbonyl, But= 0-tert-butyl group, cAMP= Adenosine 3',5'-cyclic monophosphate, DCM = Dichloromethane, DMF = N,N-Dimethylformamide, DIPCDI= Di-isopropylcarbodiimide, DIPEA= Diisopropylethylamine, 4-DBF=4-dibenzofuran-Phe-OH residue, 4-DBT=4-dibenzothiophene-Phe-OH residue, Dihydro-Phen=2-(9,10-Dihydro-phenanthrenyl]-Ala-OH residue, Et = Ethyl, Et20 = Diethyl ether, Fmoc = Fluorenylmethoxycarbonyl, 2-Flu=2-Fluorenyl-Ala-OH residue, g = Gram (s), GTT = Glucose Tolerance Test, GLP-1R = Glucagon Like Peptide-1 Receptor, h = Hour (s), HOBt = Hydroxybenzotriazole, HOAT= 7-Aza-hydroxybenzotriazole, HBTU = 2-(1H-benzotriazole-l-yl)-1,1,3,3-tetramethyl aminium hexafluorophosphate, HPLC = High Performance Liquid Chromatography, L = Liter, LC /MS = Liquid Chromatography / Mass Spectrometry, 4-(2'-Me-Ph)-3-Pyr-Ala= 4-(2'-methylphenyl)-3-pyridylalanine residue, Me = Methyl, .
Min = minute (s), m1= milliliter, l = microliter, mg = milligram (s), mmol = millimole (s), fino1= fantomolar MS= Mass Spectrometry, 1-Nap=4-(1-Naphthyl)-Phe residue, 2-Nap=4-(2-Naphthyl)-Phe residue, Phen=2-(Phenanthrenyl)-Ala-OH residue, Pbf-- Pentamethylbenzofuran-5-sulfonyl, PyBOP = Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, SPPS = Solid Phase Peptide Synthesis, Sc = sub-cutaneous, TrPh=4-phenyl-biphenylalanine residue, TMS = Trimethylsilyl, TIPS = Triisopropylsilane, TFA = Trifluoroacetic acid, TBTU= 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate, Trt= Trityl group, ((x-Me)Phe(2-F)~ a-methyl-2-fluoro-phenylalanine residue, -(N(Me))-= N-methylated amide bond, D-Alanine represented by 'a' and D-Bip represent 'D'-Biphenyl alanine residue, ip = intra-peritoneal, Sequence of GLP-1 peptide =
NH2-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-CONHZ (30 amino acids). The 30 amino acids of said GLP-1 peptide are shown in Seq ID 1.
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR ---Seq ID 1 Sequence of Exendin-4 =
NH2-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-CONH2 (39 amino acids). The 39 amino acids of Extendin -4 are shown in Seq ID 2.
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS ---Seq ID 2 Detailed description In accordance with the present invention, synthetic GLP-1 analog peptides /
peptidomimetics are provided, which have the structural formula (I), A-Xi- SI-Y-S2-X2-B (1) wherein, A represents NH-Rl, wherein Rl represents hydrogen, groups selected from linear or branched (CI-C15) alkyl chain, such as methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, decyl groups and the like, an amino acid or peptide containing one, two or three natural amino acid residues, R3-CO-group, such as (2-Hydroxy-phenyl)-acetyl group and the like, R30-C(O)- group, such as Fmoc group and the like, a sulfonyl group of formula R3-S02-, each of these groups may be substituted, wherein R3 is selected from linear or branched (Cl-Clo) alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, decyl groups and the like, (C3-C6) cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups and the like, aryl groups selected from phenyl, napthyl, indanyl, fluorenyl, biphenyl and the like, heteroaryl groups selected from pyridyl, thienyl, furyl, imidzolyl, benzofuranyl and the like, arylalkyl groups selected from benzyl, naphthylmethyl and the like, each of these groups may be substituted;

B represents -COOR2, -CONHR2 or CH2OR2, R2 represents H, groups selected from linear or branched (Cl-Clo) alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, decyl groups and the like, aryl groups selected from phenyl, napthyl, indanyl, fluorenyl, biphenyl and the like, aralkyl groups, each of these groups may be substituted, each of S1 and S2 may independently be a bond or independently represents a group '-NH-(CH2)õ-COO-', where, n=1-9; such as derivatives of amino acetic acid, amino propionic acid, amino butanoic acid, amino pentanoic acid, amino hexanoicacid, amino heptanoic acid, amino octanoic acid, amino-nonanoic acid, amino-decanoic acid and the like;
Y represents a bond or -CO-, -(CH2)m- (m = 1-3), '0', 'S', -CO-NH-, -CO-NR4-, or represents a short peptide containing one or two or three amino acids selected from natural or non-natural amino acids; where R4 represents H, optionally substituted groups selected from linear or branched (C1-CIo) alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, iso;-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, decyl groups and the like, aryl groups selected from phenyl, napthyl, indanyl, fluorenyl, biphenyl and the like; with the proviso that i) when SI-Y-SZ represents a bond, Xl is selected from the following amino acid sequences HAEGTFTSD (Seq ID 3), HAEGTFTSDV (Seq ID 4), HAEGTFTSDVS (Seq ID 5), HAEGTFTSDVSS (Seq ID 6), HAEGTFTSDVSSY (Seq ID 7), HAEGTFTSDVSSYL (Seq ID 8), HAEGTFTSDVSSYLE (Seq ID 9), HAEGTFTSDVSSYLEG (Seq ED 10), HAEGTFTSDVSSYLEGQ (Seq ID 11), HAEGTFTSDVSSYLEGQA (Seq ID 12), HAEGTFTSDVSSYLEGQAA (Seq ID 13), HAEGTFTSDVSSYLEGQAAK (Seq ID 14), HAEGTFTSDVSSYLEGQAAKE (Seq ID 15), HAEGTFTSDVSSYLEGQAAKEF (Seq ID - 16), HAEGTFTSDVSSYLEGQAAKEFI (Seq ID 17), with the further option that one or more of these amino acids may be replaced by unnatural amino acids, and X2 is selected from the following amino acid sequences GPSSGAPPPS (Seq ID 18)or KELEKLL (Seq ID 19)or GPPS or (Seq ID 20) VKGR (Seq ID 21);
ii) and when SI-Y-S2 does not represent a bond Xl is selected from the following amino acid sequences HA (Seq ID 22), HAE (Seq ID 23), HAEG (Seq ID 24), HAEGT (Seq ID 25), HAEGTF (Seq ID 26), HAEGTFT (Seq ID 27), HAEGTFTS (Seq ID 28), HAEGTFTSD (Seq ID 29) with the further option that one or more of these amino acids may be replaced by unnatural amino acids; X2 is selected from GPSSGAPPPS (Seq ID 18) or KELEKLL (Seq II) 19)or GPPS (Seq ID 20)or VKGR (Seq ID 21)or a dipeptide, selected from combination of two amino acids, consisting of natural or unnatural amino acids, having a side chain containing an arylalkyl or heteroarylalkyl moieties selected from benzyl, napthylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, isooxazolylmethyl, quinolylmethyl, benzofuranylmethyl, benzothienylmethyl, indolinylmethyl, indolylmethyl, dibenzofuranylmethyl, dibenzothienylmethyl, benzodihydrofuranylmetliyl, benzodihydrothienylmethyl, thienopyrimidylmethyl, benzimidazolylmethyl, phenanthrenylmethyl, dihydrophenanthrenylmethyl, fluorenylmethyl, dibenzofuranylmethyl, dibenzothiophenyl methyl groups and the like, where each of these groups may be optionally substituted with (CI-C6)alkyl group such as methyl, ethyl, propyl, isopropyl, n=butyl, iso-butyl, t-butyl, pentyl, isopentyl, hexyl groups and the like, (CI-C6)alkoxy group such as methoxy, ethoxy, propoxy, butoxy, pentoxy, hexanoxy groups, cyano, halo group such as chloro, bromo, iodo, fluoro groups, hydroxy or optionally substituted aryl or heteroaryl groups selected from phenyl, napthyl, pyridyl, thienyl, furyl, imidazolyl, isooxazolyl, quinolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, dibenzofuranyl, dibenzothienyl, benzodihydrofiiranyl, benzodihydrothienyl, thienopyrimidyl, benzimidazolyl, phenanthrenyl, dihydrophenanthrenyl, fluorenyl, dibenzofuranyl, dibenzothiophenyl and the like, with the further provision that such aryl or heteroaryl substituents may further be optionally substituted with (CI-C6)alkyl, (Cl-C6)alkoxy, cyano, halo, hydroxy or aryl or heteroaryl groups.
In a preferred embodiment, the dipeptide sequence may comprise of one or more amino acids selected from Bip, Bip(2-Me), Bip(2-Et), Bip(2-Ipr), Bip(2-CN), Bip(2'-Et-4'-OMe), Bip(4'-fluoro), Bip(4'-Phenyl), 2-(9,10-Dihydro-phenanthrenyl]-Ala, 2-(Phenanthrenyl)-Ala, 4=(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Fluorenyl-Ala, 4-dibenzofuran-Phe, 4-dibenzothiophene-Phe, 4-(2'-methylphenyl)-3-pyridylalanine;
The term 'natural amino acids' indicates all those twenty amino acids, which are present in nature.
The term 'unnatural amino acids' or 'non-natural amino acids' represents either replacement of L-amino acids with corresponding D-amino acids such as replacement of L-Ala with D-Ala or L-Pro with D-Pro and the like or suitable modifications of the L
or D amino acids, amino alkyl acids, either by - a-alkylation such as substitution of Ala with a-methyl Ala (Aib), replacement of Phe with a-methyl Phe, replacement of substituted Bip with with a-methyl Bip;
- N-alkylation with groups selected from (Cl-C6)alkyl or (C3-C6)cycloaikyl groups;
- modification of side chain such as replacement of His with histidine analogs such as 1-imidazolyl-alanine (II) or des-amino-His, N
N
H2N~OH
a (II) or replacement of phenyl ring of Phe with pyridyl, napthyl, biphenyl groups;
substitution on the side chain of amino acid such as substitution of aromatic amino acid side chain with halogen, (Cl-C3)alkyl, aryl groups, more specifically the replacement of Phe with 2 & 4-halo Phe;
Such 'unnatural amino acids' or 'non-natural amino acids' may be represented generally by the following structure:

R6\ N yOH
H
R
O
(Ila) wherein R5 is selected from H, F, (C1-C5) alkyl, the stereochemical configuration at the carbon bearing R5 may be (R) or (S); R5 is selected from H or (C1-C3) alkyl;
each of R7 and R8 is independently selected from H, (Cl-C3) alkyl, such as methyl and ethyl or halogen atom, preferably fluorine atom; R9 represents groups, selected from (CI-C5) alkyl, aryl or heteroryl moieties selected from phenyl, napthyl, pyridyl, thienyl, furyl, imidazolyl, isooxazolyl, quinolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, dibenzofuranyl, dibenzothienyl, benzodihydrofuranyl, benzodihydrothienyl, thienopyrimidyl, benzimidazolyl, phenanthrenyl, dihydrophenanthrenyl, fluorenyl, dibenzofuranyl, dibenzothiophenyl groups, where each of these groups may be optionally substituted with (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo, hydroxy or optionally substituted aryl or heteroaryl groups, with the further provision that such aryl or heteroaryl substituents may further be optionally substituted with (CI-C6)alkyl, (Cl-C6)alkoxy, cyano, halo, hydroxy or aryl or heteroaryl groups.

List of Fmoc protected Bip analogs used for the synthesis of GLP-1 peptidomimetics \~ /lo / /~
\
\ f_ \ ~ \ \ ~ C N

iv Fmoc-N OH
Fmoc-H OH OH
Fmoc-N

Fmoc-4-(2'-methylphenyl)-3-pyridylalanine-OH Fmoc-Bip(2'-Et- 4'-OMe)-OH Fmoc-Bip(2-CN)-OH

~ I / ~ / ~
/ I \ I \ \ I \
\

Fmoc-H OH
Fmoc-N OH Fmoc--H OH
O H O
Fmoc-Bip(2-Me)-OH Fmoc-Bip-OH Fmoc-Bip(2-Ipr)-OH
/ ~ \ ~

\ \ I \ I \ ~
Fmoc--N OH OH Fmoc~
H O Fmoc-H H COOH
O
Fmoc-Bip(2-Et)-OH Fmoc-4-(1-Naphthyl)-Phe-OH Fmoc-2-(9,10-Dihydro-phenanthrenyl]-/ \ ~ / F Ala-OH
Fmoc-N OH Fmoc-H OH Fmoc, N COOH

Fmoc-Bip(4-Ph)-OH Fmoc-Bip(4-F)-OH Fmoc-2-(Phenanthrenyl)-AIa-OH
Ih' O bu Fmoc~N COOH
H Fmoc-H OH Fmoc-H OH
Fmoc-2-Fluorenyl-Ala-OH 0 0 Fmoc-4-dibenzofiiran-Phe-OH
Fmoc-4-dibenzothiophene-Phe-OH

The suitable substituents include, but are not limited to the following radicals, alone or in combination with other radicals - hydroxyl, oxo, halo, thio, nitro, amino, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, carboxylic acid and its derivatives such as esters and amides;
The various groups, radicals and substituents used anywhere in the specification are described in the following paragraphs.
5- The term "alkyl" used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing one to ten carbons, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-ainyl, n-pentyl, n-hexyl, iso-hexyl, heptyl, octyl, decyl and the like.
The term "cycloalkyl" used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term "aryl" or "aromatic" used herein, either alone or in combination with other radicals, denotes an aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like.
The term 'arylalkyl" denotes an alkyl group, as defined above, attached to an aryl, such as benzyl, phenylethyl, naphthylmethyl, and the like. The term "aryloxy"
denotes an aryl radical, as defined above, attached to an alkoxy group, such as phenoxy, naphthyloxy and the like, which may be substituted.
The term "aralkoxy" denotes an arylalkyl moiety, as defined above, such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, and the like, which may be substituted.
The term "heteroaryl" or "heteroaromatic" used herein, either alone or in combination with other radicals, denotes an aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused containing one or more hetero atoms selected from 0, N or S, such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidinyl, pyrazolopyrimidonyl, azaquinazolinyl, azaquinazolinoyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, thieiiopyrimidonyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, quinazolonyl, pyrimidonyl, pyridazinyl, triazinyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, and the like.
The term "heteroaralkyl" used herein, either alone or in combination with other radicals, denotes a heteroaryl group, as defined above, attached to a straight or branched saturated carbon chain containing 1 to 6 carbons, such as (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-l-(2-pyrimidyl)ethyl and the like. The terms "heteroaryloxy", "heteroaralkoxy", "heterocycloxy denotes heteroaryl, heteroarylalkyl, groups respectively, as defined above, attached to an oxygen atom.
. The term "acyl" used herein, either alone or in combination with other radicals, denotes a radical containing one to eight carbons such as formyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted.
The term "carboxylic acid" used herein, alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides. The term "ester" used herein, alone or in combination with other radicals, denotes -COO- group, and includes carboxylic acid derivatives, where the ester moieties are alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may be substituted.
Unless otherwise indicated, the term 'amino acid' as employed herein alone or as part of another group includes, without limitation, an amino group and a carboxyl group linked to the same carbon, referred to as 'a' carbon.
The absolute 'S' configuration at the 'a' carbon is commonly referred to as the 'L' or natural configuration. The 'R' configuration at the 'a' carbon is commonly referred to as the 'D' amino acid. In the case where both the 'a-substituents' is equal, such as hydrogcn or niethyl, the aniino acids are Gly or Aib and are not chiral.
The term 'receptor modulator' refers to a compound that acts at the GLP-1 receptor to alter its ability to regulate downstream signaling events. Example of receptor modulators includes agonist, partial agonist, inverse agonist, allosteric potentiators.
Preferably, the isolated peptidomimetics are a 3-30 mer and such peptide bind to and activates the GLP-1 receptor.
In accordance with the present invention, the synthetic isolated peptidomiinetics described herein possess the ability to mimic the biological activity of GLP-1 peptide, with preference for agonist activity at GLP-1R. These synthetic peptidomimetics GLP-1 mimetic exhibit desirable in-vivo properties, thus making them ideal therapeutic candidates for oral or parenteral administration.
The present invention provides for compounds of formula (I) pharmaceutical compositions employing such compounds either alone or in combination and for methods of using such compounds. In particular, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), alone or in combination(s), with a pharmaceutically acceptable carrier.
Further provided is a method for treating or delaying the progression or onset of diabetes, especially type II diabetes, including complications of diabetes, including retinopathy, neuropathy, nephropathy and delayed wound healing and related diseases such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, syndrome X, atherosclerosis and hypertension, wherein a therapeutica'lly effective amount of a compound of formula (I) or their combination(s) are administered to a mammal, example, human, a patient in need of treatment.
Several synthetic routes can be employed to prepare the compounds of the present invention well known to one skilled in the art of peptide synthesis. The compounds of formula (I), where all symbols are as defined earlier can be synthesized using the methods described below, together with conventional techniques known to those skilled in the art of peptide synthesis, or variations thereon as appreciated by those skilled in the art. Referred methods include, but not limited to those described below.
The peptidomimetics thereof described herein 'may be produced by chemical synthesis using suitable variations of various solid-phase techniques generally known such as those described in G. Barany & R. B. Merrifield, "The peptides:
Analysis, synthesis, Biology"; Volume 2- "Special methods in peptide synthesis, Part A", pp. 3-284, E. Gross & J. Meienhofer, Eds., Academic Press, New York, 1980; and in J.
M.
Stewart and J. D. Young, "Solid-phase peptide synthesis" 2nd Ed., Pierce chemical Co., Rockford, Il, 1984.
The preferred strategy for preparing the peptidomimetics of this invention is based on the use of Fmoc-based SPPS approach, wherein Fmoc (9-Fluorenyl-methyl-methyloxycarbonyl) group is used for temporary protection of the a-amino group; in combination with the acid labile protecting groups, such as t-butyloxy carbonyl (Boc), tert-butyl (Bu), Trityl (Trt) group for temporary protection of the amino acid side chains (see for example E. Atherton & R.C. Sheppard, "The Fluorenyhnethoxycarbonyl amino protecting group", in "The peptides: Analysis, synthesis, Biology";
Volume 9 -"Special methods in peptide synthesis, Part C", pp. 1-38, S. Undenfriend & J.
Meienhofer, Eds., Academic Press, San Diego, 1987).

Examples of orthogonally protected amino acids used in Fmoc-solid phase peptide synthesis for the synthesis of peptidomimetics I ~ o ~ Fmoc =

ut rt N O O ~ut O
N

Fmoc-NH OH Fmoc-NH OH Fmoc=NH OH
U O O
Fmoc-His(Trt)=OH Fmoc-Glu(But)-OH Fmoc-Tltr(But)-OH

~uc ~But Boc O U

Fmoc-NH OH Fmoc-NH OH
Finac-NH OH
O
O
Fmoc-Ser(But)-OH Fmoc-Asp(But)-OH Fmoe-Lys(Boc)-OH
H
Pbi'N~NH Boc\
O .Irt . '' .
Fmoc-NH OH Fmoc-NH OH
Fmoc NII OI3 O
O
Fmoc-Gln(Trt)-OH Fmoc-Arg(Pb fl-OH Fmoc-Trp(Boc)-OH

The peptidomimetics can be synthesized in a stepwise manner on an insoluble polymer support (resin), starting form the C-terminus of the peptide. In an embodiment, the synthesis is initiated by appending the C-terminal amino acid of the peptide to the resin through formation of an amide, ester or ether linkage. This allows the eventual release of the resulting peptide as a C-terminal amide, carboxylic acid or alcohol, respectively.
In the Fmoc-based SPPS, the C-terminal amino acid and all other amino acids used in the synthesis are required to have their a-amino groups and side chain functionalities (if present) differentially protected (orthogonal protection), such that the a-amino protecting group may be selectively removed during the synthesis, using suitable base such as 20% piperidine solution, without any premature cleavage of peptide from resin or deprotection of side chain protecting groups, usually protected with the acid labile protecting groups.
The coupling of an amino acid is performed by activation of its carboxyl group as an active ester and reaction thereof with unblocked a-amino group of the N-terminal amino acid appended to the resin. After every coupling and deprotection, peptidyl-resin was washed with the excess of solvents, such as DMF, DCM and diethyl ether.
The sequence of a-amino group deprotection and coupling is repeated until the desired peptide sequence is assembled. The peptide is then cleaved from the resin with concomitant deprotection of the side chain functionalities, using an appropriate cleavage mixture, usually in the presence of appropriate scavengers to limit side reactions. The resulting peptide is finally purified by reverse phase HPLC.
The synthesis of the peptidyl-resins required as precursors to the final peptides utilizes commercially available cross-linked polystyrene polymer resins (Novabiochem, San Diego, CA). Preferred for use in this invention are Fmoc-PAL-PEG-PS resin, 4-(2', 4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetylp-methyl benzhydrylamine resin (Fmoc-Rink amide MBHA resin), 2-chloro-Trityl-chloride resin or p-benzyloxybenzyl alcaliol resin (H1VTP resin) to wliich the (_"-terrnirtal amirzo acid may or may not be already attached. If the C-terminal amino acid is not attached, its attachment may be achieved by HOBt active ester of the Fmoc-protected amino acid formed by its reaction with DIPCDI. In case of 2-Chloro-trityl resin, coupling of first Fmoc-protected amino acid was achieved, using DIPEA. For the assembly of next amino acid, N-terminal protection of peptidyl resin was selectively deprotected using a solution of 10-20 % piperidine solution. After every coupling and deprotection, excess of amino acids and coupling reagents was removed by washed with a DMF, DCM and ether.
Coupling of the subsequent amino acids can be accomplished using HOBt or HOAT active esters produced from DIPCDI/ HOBt or DIPCDI/HOAT, respectively. In case of some difficult coupling, especially coupling of those amino acids, which are hydrophobic or amino acids with bulky side chain protections, complete coupling can be achieved using a combination of highly efficient coupling agents such as HBTU, PyBOP or TBTU, with additives such as DIPEA.

General Scheme for Fmoc-Based SPPS:
Me O
H ~
O/ O O-PEG-PS--q MeO Fmoc-PAL-PEG-PS Resin 20% Piperidine Deprotection Me0 O

H2N O ~
O 4 O-PEG-PS--*
MeO Fmoc-PAL-PEG-PS Resin Fmoc,,, N Y OH Acylation H HOBt & DIPCDI
O
R Me O
Fmoc~ HN ( H O 4 O-PEG-PS---!
O
MeO

Deprotection Acylation Final cleavage with TFA mixture Peptide + Resin The synthesis of the peptide analogs described herein can be carried out by using batchwise or continuos flow peptide synthesis apparatus. The non-natural non-commercial amino acids present at different position were incorporated into the peptide chain, using one or more methods known in the art. In one approach, a Fmoc-protected non-natural amino acid was prepared in solution, using appropriate literature procedures. For example, the Fmoc-protected Bip analogs, described above, were prepared using modified Suzuki cross coupling method, as known in literature (for e.g.
Tetrahedron Letter 58, 9633-9695, 2002). The Fmoc-protected a-methylated amino acids were prepared using asymmetric Strecker synthesis, as described for e.g.
in Org.
Letters 3(8), 1121-1124, 2001. The Fmoc-protected N-methylated amino acids were prepared using a literature method as described in for e.g. JOC, 2005, 70, 6918-6920.
The resulting derivative was then used in the step-wise synthesis of the peptide.
Alternatively, the required non-natural amino acid was built on the resin directly using synthetic organic chemistry procedures and a linear peptide chain were build.
The peptide-resin precursors for their respective peptidomimetics may be cleaved and deprotected using suitable variations of any of the standard cleavage procedures described in the literature (see, for example, D. S. King et al.
Int. J. peptide Protein res. 36, 1990, 255 - 266). A preferred method for use in this invention is the use of TFA cleavage mixture, in the presence of water and TIPS as scavengers.
Typically, the peptidyl-resin was incubated in TFA / Water /TIPS (94:3:3; V: V: V; 10 ml mg of peptidyl resin) 'for 1.5-2 hrs at room temperature. The cleaved resin is then filtered off, the TFA solution is concentrated or dried under reduced pressure. The resulting crude peptide is either precipitated or washed with Et20 or is re-dissolved directly into DMF or 50 % aqueous acetic acid for purification by preparative HPLC.
Peptidomimetics with the desired purity can be obtained by purification using preparative HPLC. The solution of crude peptide is injected into a semi-Prep co lumn (Luna 10 ; C18; 100 A), dimension 250 X 50 mm and eluted with a linear gradient of ACN in water, both buffered with 0.1 % TFA, using a flow rate of 15 -50 ml /min with effluent monitoring by PDA detector at 220 nm. The ' structures of the purified peptidomimetics can be confirmed by Electrospray Mass Spectroscopy (ES-MS) analysis.
All the peptide prepared were isolated as trifluoro-acetate salt, with TFA as a counter ion, after the Prep-HPLC purification. However, some peptides were subjected for desalting, by passing through a suitable ion exchange resin bed, preferably through anion-exchange resin Dowex SBR P(Cl) or an equivalent basic anion-exchange resin. In some cases, TFA counter ions were replaced with acetate ions, by passing through suitable ion-exchange resin, eluted with dilute acetic acid solution. For the preparation of the hydrochloride salt of peptides, in the last stage of the manufacturing, selected peptides, with the acetate salt was treated with 4 M
HCl. The resulting solution was filtered through a membrane filter (0.2 m) and subsequently lyophilized to yield the white to off-white HCI salt. Following similar techniques and/or such suitable modifications, which are well within the scope of persons skilled in the art, other suitable pharmaceutically acceptable salts of the peptidomimetics of the present invention were prepared.
In a preferred embodiment, the present invention provides a method of making a peptidomimetics that mimics the activity of an endogenous polypeptide GLP-1R
agonist. In another preferred embodiment, the polypeptide receptor agonist is GLP-1.
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients as are well known.
The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) either alone or combination, according to this invention.
The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration.
By way of guidance, the daily oral dosage of the active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day and most preferably between about 0.6 to 20 mg/kg/day.
General method of preparation of peptidomimetics, using SPPS approach:
Assembly of peptidomimetics on resin:
Sufficient quantity (50-100 mg) of Fmoc-PAL-PEG-PS resin or Fmoc-Rink amide MBHA resin, loading: 0.5-0.6 mmol / g was swelled in DMF (1-10 ml /100 mg of resin) for 2-10 minutes. The Fmoc-group on resin was then removed by incubation of resin with 10-30 % piperidine in DMF (10-30 ml / 100 mg of resin), for 10-minutes. Deprotected resin was filtered and washed excess of D1VIF, DCM and ether (50 ml X 4). Washed resin was incubated in freshly distilled DMF (1 mi / 100 mg of resin), under nitrogen atmosphere for 5 minutes. A 0.5 M solution of first Fmoc-protected amino acid (1-3 eq.), pre-activated with HOBt (1-3 eq.) and DIPCDI
(1-2 eq.) in DMF was added to the resin, and the resin was then shaken for 1-3 hrs, under nitrogen atmosphere. Coupling completion was monitored using a qualitative ninhydrin test. After the coupling of first amino acid, the resin was washed with DMF, DCM and Diethyl ether (50 ml X 4). For the coupling of next amino acid, firstly, the Fmoc-protection on first amino acid, coupled with resin was deprotected, using a 10-20%
piperidine solution, followed by the coupling the Fmoc-protected second amino acid, using a suitable coupling agents, and as described above. The repeated cycles of deprotection, washing, coupling and washing were performed until the desired peptide chain was assembled on resin, as per general scheme above.
Finally, the Fmoc-protected peptidyl-resin prepared above was deprotected by 20% piperidine treatment as described above and the peptidyl-resins were washed with DMF, DCM and Diethyl ether (50 ml X 4). Resin containing desired peptide was dried under nitrogen pressure for 10-15 minutes and subjected for cleavage/
deprotection.
Cleavage and deprotection:
The desired peptidomimetics were cleaved and deprotected from their respective peptidyl-resins by treatment with TFA cleavage mixture as follows.
A
solution of TFA / Water / Triisopropylsilane (95: 2.5: 2.5) (10 ml / 100 mg of peptidyl-resin) was added to peptidyl-resins and the mixture was kept at room temperature with occasional starring. The resin was filtered, washed with a cleavage mixture and the combined filtrate was evaporated to dryness. Residue obtained was dissolved in 10 ml of water and the aqueous layer was extracted 3 times with ether (20 ml each) and finally the aqueous layer was freeze-dried. Crude peptide obtained after freeze-drying was purilied by preparative HPLC as follows:
Preparative HPLC purificat.ioa of the crude peptidomimetics:
Preparative HPLC was carried out on a Shimadzu LC-8A liquid chromatograph.
A solution of crude peptide dissolved in DMF or water was injected into a semi-Prep column (Luna 10 ; C18; 100 A ), dimension 250 X 50 mm and eluted with a linear gradient of ACN in water, both buffered with 0.1 % TFA, using a flow rate of ml / min, with effluent monitoring by PDA detector at 220 nm. A typical gradient of 20 % to 70 % of water-ACN mixture, buffered with 0.1 % TFA was used, over a period of 50 minutes, with 1% gradient change per minute. The desired product eluted were collected in a single 10-20 ml fraction and pure peptidomimetics were obtained as amorphous white powders by lyophilisation of respective HPLC fractions.
HPLC analysis of the purified peptidomimetics After purification by preparative HPLC as described above, each peptide was analyzed by analytical RP-HPLC on a Shimadzu LC-10AD analytical HPLC system.
For analytic HPLC analysis of peptidomimetics, Luna 5 ; C18; 100 A, dimension X 4.6 mm column was used, with a linear gradient of 0.1 % TFA and ACN buffer and the acquisition of chromatogram was carried out at 220 nm, using a PDA
detector.
Characterization by Mass Spectrometry Each peptide was characterized by electrospray ionisation mass spectrometry (ESI-MS), either in flow injection or LC/MS mode. Triple quadrupole mass spectrometers (API-3000 (MDS-SCIES, Canada) was used in all analyses in positive and negative ion electrospray mode. Full scan data was acquired over the mass range of quadrupole, operated at unit resolution. In all cases, the' experimentally measured molecular weight was within 0.5 Daltons of the calculated monoisotopic molecular weight. Quantification of the mass chromatogram was done using Analyst 1.4.1 software.
Utilizing the synthetic methods described herein along with other commonly known techniques and suitable variations thereof, the following GLP-1 . peptidomimetics were prepared. This list is indicative of the various groups of peptidomimetics, which can be prepared according to the present invention, and are expected to at least include obvious variations of these compounds. However, such disclosure should not be construed as limiting the scope of the invention in any way.
Table 1:
S. Sequence No.
1 HGEGTFTSD-(CH2)3-GPSSGAPPPS
2 HGEGTFTSD-(CH2)4-GPSSGAPPPS
3 HGEGTFTSD-(CH2)5-GPSSGAPPPS
4 HGEGTFTSD-(CH2)6-GPSSGAPPPS
5 HGEGTFTSD-(CH2)7-GPSSGAPPPS
6 HGEGTFTSD-(CH2)lo-GPSSGAPPPS
7 HGEGTFTSD-(CH2)11-GPSSGAPPPS

8 HGEGTFTSDLSKQM-(CH2)3-GPSS
9 HGEGTFTSDLSKQM-(CH2)4-GPSS
HGEGTFTSDLSKQM-(CH2)5-GPSS
11 HGEGTFTSDLSKQM-(CH2)6-GPSS
12 HGEGTFTSDLSKQM-(CH2)7-GPSS
13 HGEGTFTSDLSKQM-(CH2)1o-GPSS
14 HGEGTFTSDLSKQM-(CHa)II-GPSS
HGEGTFTSDLSKQME-G-GPSSGAPPPS
16 HGEGTFTSDLSKQME-(CH2)2-GPSSGAPPPS
17 HGEGTFTSDLSKQME-(CH2)3-GPSSGAPPPS
18 HGEGTFTSDLSKQME-(CH2)4-GPSSGAPPPS
19 HGEGTFTSDLSKQME-(CH2)5-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)6-GPSSGAPPPS
21 HGEGTFTSDLSKQME-(CH2)7-GPSSGAPPPS

22 HGEGTFTSDLSKQME-(CH2)lo-GPSSGAPPPS

23 HGEGTFTSDLSKQME-(CH2)11-GPSSGAPPPS
Table 2:
S. Sequence No.
1 HAEGTFTSD-(CH2)2-VKGR
2 HAEGTFTSD-(CH2)3-VKGR
3 HAEGTFTSD-(CH2)4-VKGR
4 HAEGTFTSD-(CH2)5-VKGR
5 HAEGTFTSD-(CH2)6-VKGR
6 HAEGTFTSD-(CH2)10-VKGR
7 HAibEGTFTSD-(CH2)2-VKGR
8 HAibEGTFTSD-(CH2)3-VKGR
9 HAibEGTFTSD-(CH2)4-VKGR
10 HAibEGTFTSD=(CHa)5-VKGR
11 HAibEGTFTSD-(CH2)6-VKGR

_22-12 HAibEGTFTSD-(CH2)io-VKGR

Table 3:
S. Sequence No.

4 HAibEGTFTSDGKELEKLL -HGEGTFTSDGKELEKLL

HAEGTFTSDVSSYLEKELEKLL

13 HaEGTFTSDVSSYLEGKELEKLL
14 HAibEGTFTSDVSSYLEGKELEKLL
HAEGTFTSDVSSYLEGKELEKLLVKG

19 HAibEGTFTSDVSSYLEGQAAKEFIKELEKLL
HAibEGT-(a-Me)Phe(2-F)-T SD V S S YLEGQAAKEFIKELEKLL
21 Des-amino-HAibEGT-(a-Me)Phe(2-F)-TSDV S SYLEGQAAKEFIKELEKLL
22 HAEGTFTSD-(CH2)3-KELEKLL
23 HAEGTFTSD-(CH2)4-KELEKLL

24 HAEGTFTSD-(CH2)5-KELEKLL
HAEGTFTSD-(CHa)6-KELEKLL
26 HA-(CH2)3-DVSSYLEGQAAKEFIKELEKLL

27 HAib-(CH2)3-DVSSYLEGQAAKEFIKELEKLL
28 HAibEGTFTSDVSSYLEGQ-(CH2)2-KBLEKLL
29 HAibEGTFTSDVSSYLEGQ-(CH2)3-KELEKLL
30 HAibEGTFTSDVSSYLE-(CH2)2-FIKELEKLL
Table 4:
S. Sequence No.
1 HGEGTFTSD-(CH2)3-Bip-Bip 2 HAibEGTFTSD-(CH2)3-Bip-Bip 3 HAibEGT-(a-Me)-Phe(2-F)-TSD-(CH2)3-Bip-Bip 4 HAEGTFTSD-G-Bip(2-Me)-Bip(2-Me) HAibEGTFTSD-G-Bip(2-Me)-Bip(2-Me) 6 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2-Me)-Bip(2-Me) 7 HAEGTFTS-G-Bip(2-Me)-Bip(2-Me) 8 HAibEGTFTS-G-Bip(2-Me)-Bip(2-Me) 9 HAibEGT-(a-Me)-Phe(2-F)-TS-G-Bip(2-Me)-Bip(2-Me) HAEGTFTS-(CH2)2-Bip(2-Me)-Bip(2-Me) 11 HAibEGTFTS-(CH2)2-Bip(2-Me)-Bip(2-Me) 12 HAibEGT-(a-Me)-Phe(2-F)-TS-(CH2)2-Bip(2-Me)-Bip(2-Me) 13 HAEGTFT-(CH2)a-Bip(2-Me)-Bip(2-Me) 14 HAibEGTFT-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGT-(a-Me)-Phe(2-F)-T-(CH2)2-Bip(2-Me)-Bip(2-Me) 16 HAEGTF-(CH2)2-Bip(2-Me)-Bip(2-Me) 17 HAibEGTF-(CH2)2-Bip(2-Me)-Bip(2-Me) 18 HAibEGT-(a-Me)-Phe(2-F)-(CH2)2-Bip(2-Me)-Bip(2-Me) 19 HAEGT-(CH2)2-Bip(2-Me)-Bip(2-IVIe) HAibEGT-(CH2)2-Bip(2-Me)-Bip(2-Me) 21 HAEG-(CH2)2-Bip(2-Me)-Bip(2-Me) 22 HAibEG-(CH2)2-Bip(2-Me)-Bip(2-Me) 23 HAEGTFTSD-(CH2)2-Bip(2-Me)-Bip(2-Me) 24 HAibEGTFTSD-(CH2)2-Bip(2-Me)-Bip(2-Me) 25 HAibEGT-(a-Me)-Phe(2-F)-TSD-(CH2)2-Bip(2-Me)-Bip(2-Me) 26 HAEGTFTSD-G-Bip-Bip(2-Me) 27 HAibEGTFTSD-G-Bip-Bip(2-Me) 28 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip-Bip(2-Me) 29 HAEGTFTSD-G-Bip(2-Me)-Bip 30 HAibEGTFTSD-G-Bip(2-Me)-Bip 31 HA.ibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2-Me)-Bip 32 HAEGTFTSD-G-Bip-Bip 33 HAibEGTFTSD-G-Bip-Bip 34 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip-Bip 35 HAEGTFTSD-G-Bip-Bip(2-Et) 36 HAibEGTFTSD-G-Bip-Bip(2-Et) 37 HAibEGT-((x-Me)-Phe(2-F)-TSD-G-Bip-Bip(2-Et) 38 HAEGTFTSD-G-Bip(2-Et)-Bip(2-Et) 39 HAibEGTFTSD-G-Bip(2-Et)-Bip(2-Et) 40 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2-Et)-Bip(2-Et) 41 HAEGTFTSD-G-Bip(2-Et)-Bip 42 HAibEGTFTSD-G-Bip(2-Et)-Bip 43 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2-Et)-Bip 44 HAEGTFTSD-G-Bip(2-Et)-Bip(2-Me) 15 HAibEGTFTSD-G-Bip(2-Et)-Bip(2-Me) 46 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2-Et)-Bip(2-Me) 47 HAEGTFTSD-G-Bip(2-Me)-Bip(2-Et) 48 11AibECi'1'.pTSD-G-13ip(2-Ivle)-Bip(2-Et) 49 HAibEGT=(a-Me)-Phe(2-F)-TSD-G-Bip(2-Me)-Bip(2-Et) 50 HGEGTFTSD-G-Bip(2-Me)-Bip(2-Me) 51 HGEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2-Me)-Bip(2-Me) 52 HGEGTFTSD-G-Bip(2-Et)-Bip(2-Et) 53 HGEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2-Et)-Bip(2-Et) 54 HGEGTFTSD-(CH2)3-Bip(2-Me)-Bip(2-Me) 55 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)3-Bip(2-Me)-Bip(2-Me) 56 HGEGTFTSD-(CH2)4-Bip(2-Me)-Bip(2-Me) 57 HGEGT-(a-Me)-Phe(2-F)-TSD-(CHa)4-Bip(2-Me)-Bip(2-Me) 58 HGEGTFTSD-(CH2)5-Bip(2-Me)-Bip(2-Me) 59 HGEGT-(a-Me)-Phe(2-F)-TSD-(CHa)5-Bip(2-Me)-Bip(2-Me) 60 HGEGTFTSD-(CH2)6-Bip(2-Me)-Bip(2-Me) 61 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)6-Bip(2-Me)-Bip(2-Me) 62 HGEGTFTSD-(CH2)lo-Bip(2-Me)-Bip(2-Me) 63 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)lo-Bip(2-Me)-Bip(2-Me) 64 HGEGTFTSD-(CH2)3-Bip(2-Et)-Bip(2-Et) 65 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)3-Bip(2-Et)-Bip(2-Et) .
66 HGEGTFTSD-(CH2)4-Bip(2-Et)-Bip(2-Et) 67 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)4-Bip(2-Et)-Bip(2-Et) 68 ),~iGEGTFTSD-(CH2)5-B ip(2-Et)-B ip(2-Et) 69 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)5-Bip(2-Et)-Bip(2-Et) 70 HGEGTFTSD-(CH2)6-Bip(2-Et)-Bip(2-Et) 71 HGEGT-(a-Me)-Phe(2-F)-TSD-(CHZ)6-Bip(2-Et)-Bip(2-Et) 72 HGEGTFTSD-(CH2)Io-Bip(2-Et)-Bip(2-Et) 73 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)lo-Bip(2-Et)-Bip(2-Et) 74 HGEGTFTSD-(CH2)11-Bip(2-Et)-Bip(2-Et) 75 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)11-Bip(2-Et)-Bip(2-Et) 76 HGEGTFTS-(CH2)3-Bip(2-Me)-Bip(2-Me) 77 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)3-Bip(2-Me)-Bip(2-Me) 78 HGEGTFTS-(CH2)4-Bip(2-Me)-Bip(2-Me) 79 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)4-Bip(2-Me)-Bip(2-Me) 80 HGEGTFTS-(CH2)5-Bip(2-Me)-Bip(2-Me) 81 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)5-Bip(2-Me)-Bip(2-Me) 82 HGEGTFTS-(CH2)6-Bip(2-Me)-Bip(2-Me) 83 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)6-Bip(2-Me)-Bip(2-Me) 84 HGEGTFTS-(CH2)lo-Bip(2-Me)-Bip(2-Me) 85 HGEGT-(a-Me)-Phe(2-F)-TS-(CHa)lo-Bip(2-Me)-Bip(2-Me) 86 HGEGTFTS-(CH2)11-Bip(2-Me)-Bip(2-Me) 87 HGEGT-(a-Me)-Phe(2-F)-TS-(CHa)11-Bip(2-Me)-Bip(2-Me) 88 HGEGTFTS-(CH2)3-Bip(2-Et)-Bip(2-Et) 89 HGEGT-(a-Me)-Phe(2-F)-TS-(CHa)3-Bip(2-Et)-Bip(2-Et) 90 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)4-Bip(2-Et)-Bip(2-Et) 91 HGEGTFTS-(CHa)4-Bip(2-Et)-Bip(2-Et) 92 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)4-Bip(2-Et)-Bip(2-Et) 93 HGEGTFTS-(CH2)5-Bip(2-Et)-Bip(2-Et) 94 HGEGT-(a-Me)-Phe(2-F)-TS-(CHZ)5-Bip(2-Et)-Bip(2-Et) 95 HGEGTFTS-(CH2)6-Bip(2-Et)-Bip(2-Et) 96 HGEGT-(a-Me) ;Phe(2-F)-TS-(CH2)6-Bip(2-Et)-Bip(2-Et) 97 HGEGTFTS-(CH2)10-Bip(2-Et)-Bip(2-Et) 98 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)lo:Bip(2-Et)-Bip(2-Et) 99 HGEGTFTS-(CH2)11-Bip(2-Et)-Bip(2-Eti) 100 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)11-Bip(2-Et)-Bip(2-Et) 101 HGEGTFTS-(CH2)2-Bip(2-Me)-Bip(2-Me) 102 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)2-Bip(2-Me)-Bip(2-Me) 103 HGEGTFTS-(CHa)2-Bip(2-Et)-Bip(2-Et) 104 HGEGT-(a-Me)-Phe(2-F)-TS-(CH2)2-Bip(2-Et)-Bip(2-Et) 105 HAEGTFTS-(CH2)2-Bip(2-Et)-Bip(2-Et) 106 HAibEGTFTS-(CHZ)a-Bip(2-Et)-Bip(2-Et) 107 HAibEGT-(a-Me)-Phe(2-F)-TS-(CH2)2-Bip(2-Et)-Bip(2-Et) 108 HGEGTFTSD-(CHa)2-Bip(2-Et)-Bip(2-Et) 109 HGEGT-(a-Me)-Phe(2-F)-TSD-(CH2)2-Bip(2-Et)-Bip(2-Et) 110 HAEGTFTSD-(CH2)2-Bip(2-Et)-Bip(2-Et) 111 HAibEGTFTSD-(CH~)2-Bip(2-Et)-Bip( 2-Et) 112 HAibEGT-(a-Me)-Phe(2-F)-TSD-(CH2)2-Bip(2-Et)-Bip(2-Et) 113 HA.EGTF-(CH2)2-Bip(2-Me)-Bip(2-Et) 114 IlAibEGTF-(CH2)2-Bip(2-Me)-Bip(2-Et) 115 HA,ibEGT-(a-Me)-Phe(2-F)-(CHZ)Z-Bip(2-Me)-Bip(2-Et) 116 HAEGTFTSD-G-TrPh-TrPh 117 HAibEGTFTSD-G-TrPh-TrPh 118 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-TrPh-TrPh 119 HAibEGT-(a-Me)-Phe(2-F)-(CH2)2-TrPh-TrPh 120 FIAibEG-(CHZ)a-TrPh-TrPh 121 HAibE-(CH2)2-TrPh-TrPh 122 HAib-(CH2)3-TrPh-TrPh 123 HAEGTFTSD-G-Nap-Nap 124 HAibEGTFTSD-G-Nap-Nap 125 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Nap-Nap 126 HAEGTFTSD-G-Bip(2-F)-Bip(2-F) 127 HAibEGTFTSD-G-Bip(2-F)-Bip(2-F) 128 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2-F)-Bip(2-F) 129 HAEGTFTSD-G-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 130 HAibEGTFTSD-G-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 131 HAibEGT-(a-Me)-Phe(2-F)-TSD-G-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 132 HAEGTFTSD-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 133 HAibEGTFTSD-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 134 HAibEGT-(a-Me)-Phe(2-F)-TSD-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 135 HAEGTFTS-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 136 HAibEGTFTS-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 137 HAibEGT-((x-Me)-Phe(2-F)-TS-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 138 HAEGTFT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 139 HAibEGTFT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 140 HAibEGT-((x-Me)-Phe(2-F)-T-(C112)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 141 HAEGTF-(CH2)Z-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 142 HAibEGTF-(CH2)2-B ip(2' -Et-4' -OMe)-4-(2' -Me-Ph)-3 -Pyr-Ala 143 HAibEGT-(a-Me)-Phe(2-F)-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 144 HAEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 145 HAibEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 146 HAEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 147 HAibEG-(CHa)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 148 HAEG-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala 149 HAibEG-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala Table 5:
S. Sequence No.
1 HAEGT-(CH2)2-Bip(2-Me)-Bip(2-Me) 2 HGEGT-(CH2)3-Bip(2-Me)-Bip(2-Me) 3 HGEGT-(CH2)4-Bip(2-Me)-Bip(2-Me) 4 HGEGT-(CHz)3=Bip(2-Me)-Bip(2-Me) HGEGT-(CH2)6-Bip(2-Me)-Bip(2-Me) 6 HAEGT-(CH2)2-Bip(2-Me)-DBip(2-Me) 7 HAEGT-(CHa)2-DBip(2-Me)-Bip(2-Me) 8 HaEGT-(CH2)2-Bip(2-Me)-Bip(2-Me) 9 HGEG-(CH2)3-Bip(2-Me)-Bip(2-Me) HAEG-(CH2)3-Bip(2-Me)-Bip(2-Me) 11 HGEG-(CH2)4-Bip(2-Me)-Bip(2-Me) 12 HGEG-(CH2)5-Bip(2-Me)-Bip(2-Me) 13 HGEG-(CH2)6-Bip(2-Me)-Bip(2-Me) 14 HAEG-(CH2)3-Bip(2-Et)-Bip(2-Me) HAEG-(CH2)3-Bip(2-Me)-DBip(2-Me) 16 HAEG-(CH2)4-Bip(2-Me)-DBip(2-Me) 17 HAEG-(CH2)5-Bip(2-Me)-DBip(2-Me) 18 HGEG-(CH2)5-DBip(2-Me)-Bip(2-Me) 19 HAE-(CH2)3-Bip(2-Me)-Bip(2-Me) HAE-(CH2)3-Bip(2-Me)-DBip(2-Me) 21 HAE-(CH2)2-D-Bip(2-Me)-Bip(2-Me) 22 HAE-(CH2)3-D-Bip(2-Me)-Bip(2-Me) 23 HAE-(CH2)4-D-Bip(2-Me)-Bip(2-Me) 24 HAE-(CH2)4-Bip(2-Me)-DBip(2-Me) HAE-(CH2)S-D-Bip(2-Me)-Bip(2-Me) 26 HAE-(CH2)3-Bip(2-Et)-Bip(2-Me) 27 HAE-(CH2)2-Bip(2-Me)-Bip(2-Me) Table 6:
S. Sequence No.
1 H-(CH2)3-Bip(2-Me)-Bip(2-Me) 2 H-(CH2)4-Bip(2-Me)-Bip(2-Me) 3 H-(CH2)$-Bip(2-Me)-Bip(2-Me) 4 H-(CH2)3-Bip(2-Et)-Bip(2-Me) H-(CH2)4-Bip(2-Et)-Bip(2-Me) 6 H-(CH2)5-Bip(2-Et)-Bip(2-Me) 7 H-(CH2)6-Bip(2-Et)-Bip(2-Me) 8 H-(CH2)lo-Bip(2-Et)-Bip(2-Me-) 9 H-(CH2)5-Bip(2-Me)-DBip(2-Me) H-(CH2)5-DBip(2-Me)-Bip(2-Me) 11 H-(CH2)5-DBip(2-Me)-DBip(2-Me) 12 HG-(CH2)3-Bip(2-Me)-Bip(2-Me) 13 HG-(CH2)4-Bip(2-Me)-Bip(2-Me) 14 HG-(CH2)3-Bip(2-Et)-Bip(2-Me) HG-(CH2)4-Bip(2-Et)-Bip(2-Me) 16 HG-(CH2)3-Bip(2-Et)-DBip(2-Me) 17 HG-(CH2)3-Bip(2-Me)-DBip(2-Me) 18 FA-(CH2)3-DBip(2-Me)-Bip(2-Et) 19 FA-(CHz)j-DBip-DBip Ha-(CH2)3-Bip(2-Me)-Bip(2-Me) 21 Ha-(CH2)4-Bip(2-Me)-Bip(2-Me) 22 Ha-(CH2)5-Bip(2-Me)-Bip(2-Me) 23 Ha-(CH2)3-Bip(2-Et)-Bip(2-Me) 24 Ha-(CH2)3-Bip(2-Et)-DBip(2-Me) Ha-(CH2)3-Bip(2-Me)-DBip(2-Me) 26 Ha-(CH2)3-Bip(2-Et)-DBip(2-Et) 27 Ha-(CH2)3-Bip(2-Me)-Bip 28 Ha-(CH2)3-(N(Me))-DBip(2-Me)-Bip(2-Et) 29 Ha-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me) 30 Ha-(CH2)3-(N(Me))-DBip-Bip(2-Et) 31 Ha-(CH2)3-DBip(2-Me)-Bip(2-Et) 32 HA-(CH2)3-Bip(2-Me)-Bip(2-Me) 33 HA-(CH2)4-Bip(2-Me)-Bip(2-Me) 34 HA-(CH2)5-Bip(2-Me)-Bip(2-Me) 35 HA-(CH2)6-Bip(2-Me)-Bip(2-Me) 36 HA-(CH2)lo-Bip(2-Me)-Bip(2-Me) 37 HA-(CH2)I1-Bip(2-Me)-Bip(2-Me) 38 HA-(CHa)3-Bip(2-Et)-Bip(2-Me) 39 HA-(CH2)3-Bip(2-Et)-DBip(2-Et) 40 HA-(CH2)3-DBip(2-Me)-DBip(2-Me) 41 HA-(CH2)3-DBip(2-Me)-Bip(2-Me) 42 HA-(CH2)3-Bip(2-Me)-DBip(2-Me) 43 HA-(CH2)3-Bip(2-Ipr)-Bip(2-Ipr) 44 HA-(CH2)3-Bip(2-Ipr)-Bip(2-Me) 45 HA-(CH2)3-Bip(2-Me)-Bip(2-Ipr) 46 HA-(CH2)4-Bip(2-Et)-Bip(2-Me) 47 HA-(CH2)3-Bip(2-Me)-DBip(2-Et) 48 HA-(CH2)2-Bip(2-Et)-Bip(2-Me) 49 HA-(CH2)5-Bip(2-Et)-Bip(2-Me) 50 HA-(CH2)6-Bip(2-Et)-Bip(2-Me) 51 HA-(CH2)2-Bip(2-Me)-Bip(2-Me) 52 HA-(CH2)3-DBip(2-Et)-DBip(2-Me) 53 HA-(CH2)3-DBip(2-Et)-Bip(2-Me) 54 HA-(CH2)2-Bip(2-Me)-DBip(2-Me) 55 HA-(CH2)3-Bip(2-Et)-Bip(2-Et) 56 HA-(CH2)3-DBip(2-Et)-DBip(2-Et) 57 HA-(CH2)3-DBip(2-Et)-Bip(2-Et) 58 HA-(CH2)3-DBip(2-Me)-DBip(2-Et) 59 HA-(CH2)3-Bip(2-Me)-Bip(2-Et) 60 HA-(CH2)3-DBip(2-Me)-Bip(2-Et) 61 HA-(CH2)3=Bip-Bip 62 HA-(CH2)3-Bip-DBip 63 HA-(CH2)3-DBip-DBip 64 HA-(CH2)3-DBip-Bip 65 HA-(CH2)3-Bip-Bip(2-Me) 66 HA-(CH2)3-Bip(2-Me)-Bip 67 HA=(CH2)3-Bip(2-Et)-Bip 68 HA-(CHa)3-Bip-Bip(2-Et) 69 HA=(CHa)3-Bip(2-Ipr)-DBip(2-Ipr) 70 HA-(CHa)3-DBip(2-Ipr)-Bip(2-Ipr) 71 HA-(CHZ)3-DBip(2-Ipr)-DBip(2-Ipr) 72 HA-(CH2)3-Bip(2-Me)-Bip(2-CN) 73 HA-(CH2)3-Bip-Bip(2-CN) 74 HA-(CH2)3-Bip(2-Et)-Bip(2-CN) 75 HA-(CH2)3-Bip(2-Ipr)-Bip(2-CN) 76 HA-(CH2)3-Bip(2-CN)-Bip(2-Me) 77 HA-(CHa)3-Bip(2-CN)-Bip 78 HA-(CH2)3-Bip(2-CN)-Bip(2-Et) 79 HA-(CH2)3-Bip(2-CN)-Bip(2-Ipr) 80 HA-(CH2)3-Bip(2-CN)-Bip(2-CN) 81 HA-(CH2)2-F-(CH2)2-Bip(2-Et)-DBip(2-Et) 82 HA-(CHa)2-F-(CH2)2-Bip(2-Et)-DBip(2-Me) 83 HA-(CH2)s-Bip(2-Me)-DBip 84 HA-(CH2)3-Bip(2-Me)-DBip-R

85 I IA-(CI I2)3-D13 ip(2-Mc)-DB ip 86 HA-(CH2)s-Bip(2-Me)-DBip(2-Me) 87 HA-(CH2)5-DBip(2-Me)-Bip(2-Me) 88 HA-(CH2)4-D(Bip)-Bip(2-Et) 89 HA-(CH2)5-D(Bip)-Bip(2-Et) 90 HA-(CH2)4-Bip(2-Me)-DBip(2-Me) 91 HA-(CH2)5-Bip(2-Me)-DBip(2-Me) 92 HA-(CH2)3-(N(Me))-DBip-Bip(2-Et) 93 HA-(CH2)4-DBip(2-Me)-Bip(2-Et) 94 HA-(CH2)5-DBip(2-Me)-Bip(2-Et) 95 HA-(CH2)3-(N(Me))-DBip(2-Me)-Bip(2-Et) 96 HA-(CH2)4-Bip(2-Me)-DBip 97 HA-(CH2)5-Bip(2-Me)-DBip 98 HA-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me) 99 HA-(N(Me))-(CH2)3-DBip(2-Me)-Bip(2-Et) 100 HA-(N(Me))-(CH2)3-DBip-Bip(2-Et) 101 HA-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me) 102 HA-(N(Me))-(CH2)3-Bip(2-Me)-DBip 103 HAE-(CH2)2-F-(CHa)2-Bip(2-Et)-DBip(2-Et) 104 HAE-(CH2)2-F-(CHa)2-Bip(2-Et)-DBip(2-Me) 105 HAib-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me) The following compounds can be prepared according to the general processes described above and are included within the scope of the present invention (Tables 7-9) Table 7:
S. Sequence No.
1 HA-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 2 H-Aib-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 3 Ha-(CHa)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 4 H-(N(Me))A-(CHa)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-6 H-(N(Me))Aib-(N(Me))-(CHa)a-Bip(2'-E1-4'-OMd)A4-(2'-Md-Ph)-3-Pyr-Ala-NHa 7 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 8 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NHa 9 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-AIa-NH2 11 Des-amino-H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH2 12 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NHa 13 H-(N(Me))A-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 14 H-(N(Me))Aib-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CHa)6-CH3 15 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-NH-(CH2)10-CH3 16 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))4-(2' -Me-Ph) -3 -Pyr-Ala-NH-(CH2) l o-CH3 17 CH3-(CH2)6-NH-(N(Me))A-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-AIa-NH-(CH2)6-CH3 18 CH3-(CHa)6-NH-(N(Me))Aib-(N(Me))-(CHZ)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-NH-(CH2)6-CH3 19 CH3-(CH2)la-NH-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3-Pyr-AIa-NH-(CH2)6-CH3 20 CH3-(CH2)lo-NH-(N(Me))Aib-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-NH-(CH2)6-CH3 21 HA-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 22 H-Aib-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 23 Ha-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr=Ala-NH2 24 Ti-(N(Me))A-(CTi1,)3-Rip(2'-Ft-4'-oMe)-4-(2'-Me-Ph)-3-Pyr-AIa-NH2 25 H-(N(Me))A-(N(Me))-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-26 H-(N(Me))Aib-(N(Me))-(CHa)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 27 H-(N(Me))A-(N(Me))-(CHZ)3-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 28 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 29 H-(N(Me))A-(N(Me))-(CHa)3-(N(Me))-Bip(2'-Et=4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 30 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH2 31 Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-NH2 -32 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH2 33 H-(N(Me))A-(N(Me))-(CHa)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 34 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)g-CH3 35 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH-(CH2)1 o-CH3 36 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)1o-CH3 37 CH3-(CH2)6-NH-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2) 6-CH3 38 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 39 CH3-(CH2)io-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-NH' (CHZ)6-CH3 40 CH3-(CH2)lo-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 41 HA-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 42 H-Aib-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 43 H-a-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 44 H-(N(Me))A-(CHy)~-Bip(2'-Rt-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-NH2 45 H-(N(Me))A-(N(Me))-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-46 H-(N(Me))Aib-(N(Me))-(CH2)4-B ip(2' -Et-4' -OMe)-4-(2' -Me-Ph)-3-Pyr-Ala-NHa 47 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 48 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NHZ
49 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH2 50 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH2 51 Des-amino-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-AIa-NH2 52 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH2 53 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-AIa-NH-(CH2)6-CH3 54 H-(N(1VIe))Aib-(N(Me))-(CH2)4-(N(.NIe))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 55 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH-(CH2)1 o-CH3 56 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)1 o-CH3 57 CH3-(CHa)6-NH-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 58 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 59 CH3-(CHa)lo-NH-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(1Wie))-4-(2' -Me-Ph)-3 -P,y r-A l a-NH-(CH2)b-tv'I I3 60 CH3-(CH2)IO-NH-H-N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CHz)6-CH3 61 HAE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala~NH2 62 H-Aib-E-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 63 HaE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 64 H-(N(Me))AE-(CHa)Z-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 65 H-(N(Me))AE-(N(Me))-(CH2)z-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NHa 66 H-(N(Me))Aib-E-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 67 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NHa 68 H-(N(Me))Aib-E-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NHa 69 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH2 70 H-(N(Me))Aib-E-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 71 Des-amino-H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OIVIe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-AIa-NH2 72 Des-amino-H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-AIa-NH2 73 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 74 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CHa)6-CH3 75 H-(N(Me))AE-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH-(CH2)1 o-CH3 76 H-(N(Me))Aib=E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-A la-N H-(CH2) l o-CH3 77 CH3-(CH2)6-NH-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 78 CII3-(CIIz)6-NII-(N(Me))Aih-E-(N(Me))-(CH2)2-(N(Me))=Bip(2'-E[-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 79 {CH3-(CH2)io-NH-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 80 CH3-(CHZ)lo-NH-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(IVIe))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 81 HAEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)=3-Pyr-Ala-NHa 82 H-Aib-EG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3=Pyr-Ala-NH2 83 HaEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-NH2 84 H-(N(Me))AEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NHa 85 H-(N(Me))AEG-(N(Me))-(CH2)a-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 86 H-(N(Me))Aib-EG-(N(Me))-(CHa)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 87 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 88 H-(N(Me))Aib-EG-(N(Me))-(CH2)Z-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NHZ
89 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 90 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-AIa-NH2 91 Des-amino-H-(N(Me))AEG-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-NH2 92 Des-amino-H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 93 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 94 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 95 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)1o-CH3 96 H-(N(Me))Aib-EG-(N(Me))-(CHZ)2-(N(Me))-13ip(2'-Et-4'-OMe)-(N(Me))-4 -(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2) l o-CH3 97 CH3-(CH2)6-NH-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NII-(CH2)6-CH3 98 CH3-(CHa)6-NH-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 99 CH3-(CH2)lo-NH-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 100 CH3-(CH2)lo-NH-(N(Me))Aib-EG-(N(Me))-(CH2)Z-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CHz)6-CH3 101 HAEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 102 H-Aib-EGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 103 HaEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 104 H-(N(Me))AEGT-(CH2)a-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 105 H-(N(Me))AEGT-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 106 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 107 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3 -Pyr-Ala-NH2 108 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3 -Pyr-AIa-NH2 109 H-(N(Me))AEGT-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NHZ

110 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH2 111 Des-amino-H-(N(Me))AEGT-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH2 112 Des-amino-H-(N(Me))Aib-EGT-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 113 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 114 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 115 H-(N(Me))AEGT-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(IVIe))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)1 o-CH3 116 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-NH-(CH2) i o-CH3 117 CH3-(CH2)6-NH-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CHa)6-CH3 118 CH3-(CHz)6-NH-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 119 CH3-(CH2)lo-NH-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))=4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 120 CH3-(CH2)lo-NH-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 121 HA-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 122 H-Aib-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 123 Ha-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 124 H-(N(Me))A-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 125 H-(N(Me))A-(N(Me))-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 126 H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 127 H-(I~T(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-Bip(2-Me)-NH2 128 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-Bip(2-Me)-NH2 129 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH2 130 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))Bip(2-Me)-(N(Me))-Bip(2-Me)-131 Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH2 132 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH2 133 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 134 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 135 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)lo-CH3 136 .!1-(1J(Me))Aib-(N(Me))-(CT T.,i)3-(N(Me))-Bila(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)io-CH3 137 CH(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 138 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 139 CH3-(CH2)Io-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-B ip(2-Me)-NH-(CH2)6-CH3 140 CH3-(CH2)lo-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-B (N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 141 HA-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 142 H-Aib-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 143 Ha-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 144 H-(N(Me))A-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 145 H-(N(Me))A-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 146 H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 147 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me)-NH2 148 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me)-NH2 149 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NHa 150 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-151 Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH2 152 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NHa 153 H-(N(Me))A-(N(Me))-(CHa)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 154 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 155 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)lo-CH3 156 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)lo-CH3 157 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bi(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 158 GH3-(CHz)6-NH-H-(hT(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 159 CH3-(CH2)lo-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et).-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 160 CH3-(CH2)lo-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 Table 8:

S. Sequence No.
1 HA-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
2 H-Aib-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
3 Ha-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
4 H-(N(Me))A-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CHa)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OTi 6 H-(N(Me))Aib-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH

7 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-B ip(2' -Et-4' -OMe)-4-(2' -Me-Ph)-3 -Pyr-Ala-OH
8 H-(N(Me))Aib-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH

9 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
11 Des-amino-H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-OH
12 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-AIa-OH
13 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-COO-(CH2)g-CH3 14 H-(N(Me))Aib-(N(Me))-(CH2)Z-(N(1VIe))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-COO-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-COO-(CH2)1o-CH3 16 H-(N(Me))Aib-(N(iVle))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2) I o-CH3 17 CH3-(CHa)6-NH-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-C OO-(CH2)6-CH3 18 CH3-(CH2)6-NH-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-O1VIe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-COO-(CH2)6-CH3 19 CH3-(CH2)lo-NH-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-C OO-(CH2)6-CH3 20 CH3-(CH2)lo-NH-(N(Me))Aib-(N(Me))-(CH2)2-(N(1VIe))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-COO-(CH2)6-CH3 21 HA-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
22 H-Aib-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
23 Ha-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
24 H-(N(Me))A-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
25 H-(N(Me))A-(N(Me))-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-1VIe-Ph)-3-Pyr-AIa-OH
26 H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
27 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-B~p(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
28 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
29 H-(N(Me))A-(N(Me))-(CHa)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
30 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
31 Des-amino-H-(N(Me))A-(N(Me))-(CHa)3-(N(Me))-Bip(2' -Et-4' -OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-OH
32 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-AIa-OH
33 H-(N(Me))A-(N(Me))-(CH2)3-(NN(Me))-Bip(2'-Et-4'-OM )-(N(Me))-4=(2'-Me-Ph)-3 -Pyr-Ala-COO-(CH2)6-CH3 34 H-(N(Ma))Aib-(N(Me))-(CHz)3-(N(Mc))-Bip(2'-Et-4'-OMe)-(N(NIe))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 35 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-AIa-COO-(CHa) la-CH3 36 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2' -Et-4' -OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-COO-(CH2) i o-CH3 37 CH3-(CH2)6-NH-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-C OO-(CH2)6-CH3 38 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))sBip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-C OO-(CH2)6-CH3 39 CH3-(CH2)Io-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-COO-(CH2)6-CH3 40 CH3-(CH2)io-NH-H-(N(Me))Aib-(N(Me))-(CHa)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me)) -4-(2' -Me-Ph)-3 -Pyr-Ala-COO-(CH2)6-CH3 41 HA-(CH2)~-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
42 H-Aib-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
43 Ha-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
44 H-(N(Me))A-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
45 H-(N(Me))A-(N(Me))-(CHa)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3=Pyr-Ala-OH
46 H-(N(Me))Aib-(N(Me))-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
47 H-(N(Me))A-(N(Me))-(CHa)4-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
48 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
49 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
50 H-(N(Me))Aib-(N(Me))-(CHZ)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
51 Des-amino-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'=OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-OH
52 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'.-Et-4'-OMe)-(N(Me)) -4-(2' -Me-Ph)-3 -Pyr-Ala-OH
53 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-COO-(CH2)6-CH3 54 H-(N(1VIe))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 55 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-COO-(CH2) t o-CH3 56 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))=4-(2'-Me-Ph)-3 -Pyr-Ala-C OO-(CH2)1 o-CH3 57 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-COO-(CH2)6-CH3 58 CH3-(CHZ)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2' -Et-4' -OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-COO-(CH2)6-CH3 59 CH3-(CH2)io-NH-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph) -3 -Pyr-Ala-COO-(CH2)6-CH3 60 'CH3-(CH2)io-NH-H-N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 =,Pyr-AIa-COO-(CHa)6-CH3 61 HAE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
62 H-Aib-E-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
63 HaE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
64 H-(N(Me))AE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
65 H-(N(Me))AE-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
66 H-(N(Me))Aib~E-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
67 H-(N(Me))AE-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
68 H-(N(Me))Aib-E-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
69 H-(N(Me))AE-(N(1VIe))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-OH
70 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
71 Des-amino-H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-OH
72 Des-amino-H-(N(Me))Aib-E-(N(Me))-(CHz)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -1VIe-Ph)-3 -Pyr-Ala-OH
73 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 74 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-COO-(CH2)6-CH3 75 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-C OO-(CH2)1 o-CH3 76 H-(N(Me))Aib-E-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-C OO-(CH2)1 o-CH3 77 CH3-(CH2)6-NH-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-COO-(CHZ)6-CHs 78 CH3-(CH2)6-NH-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-B ip(2' -Et-4' -OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-COO-(CHa)6-CH3 79 CH3-(CH2)io-NH-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-AIa-COO-(CH2)6-CH3 80 CH3-(CH2)lo-NH-(N(Me))Aib-E-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-COO-(CH2)6-CH3 81 HAEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
82 H-Aib-EG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
83 HaEG-(CH2)a-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
84 H-(N(Me))AEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
85 H-(N(Me))AEG-(N(Me))-(CHa)a-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
86 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
87 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
88 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
89 H-(N(Me))AEG-(N(Me))-(CHZ)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
90 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-OH
91 Des-amino-H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-OH
92 Des-amino-H-(N(Me))Aib-EG-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph) -3 -Pyr-Ala-OH
93 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 94 H-(N(Me))Aib-EG-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-' (2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 95 H-(N(Me))AEG-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-C OO-(CH2)1 o-CH3 96 H-(N(Me))Aib-EG-(N(Me))-(CHz)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-C OO-(CHa) l o-CH3 97 CH3-(CH2)6-NH-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-COO-(CH2)6-CH3 98 CH3-(CH2)6-NH-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 99 CH3-(CH2)lo-NH-(N(Me))AEG-(N(Me))-(CHz)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 Pyr-AIa-COO-(CH2)6-CH3 100 CH3-(CH2)lo-NH-(N(Me))Aib-EG-(N(Me))-(CH2)z-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CHa)6-CH3 101 HAEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-AIa-OH
102 H-Aib-EGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'=Me-Ph)-3-Pyr-AIa-OH
103 HaEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
104 HL(N(Me))AEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
105 H-(N(Me))AEGT-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
106 H-(N(Me))Aib-EGT-(N(Me))-(CH2)a-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
107 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
108 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3 -Pyr-Ala-OH
109 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
110 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-OH
11.1 Des-amino-H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Al a-OH
112 Des-amino-H-(N(Me))Aib-EGT-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-OH
113 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-AIa-COO-(CH2)6-CH3 114 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-AIa-COO-(CH2)6-CH3 115 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-COO-(CH2)1 o-CH3 116 H-(N(Me))Aib-EGT-(N(Me))-(CH2)Z-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CHa) Io-CH3 117 CH3-(CH2)6-NH-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-C OO-(CH2)6-CH3 118 CH3-(CH2)6-NH-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4=(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 119 CH3-(CH2)lo-NH-(N(Me))AEGT-(N(Me))-(CH2)a-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2' -Me-Ph)-3 -Pyr-Ala-C OO-(CH2)6-CH3 120 CH3-(CH2)10-NH-(N(Me))Aib-EGT-(N(Me))-(CHa)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 121 HA-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
122 H-Aib-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
123 Ha-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
124 H-(N(Me))A-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
125 H-(N(Me))A-(N(Me))-(CH-1)3-Bip(2-Me)->:iip(2-Me)-OH
126 H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
127 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-Bip(2-Me)-OH
128 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-Bip(2-Me)-OH
129 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-OH
130 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-OH
131 Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-OH
132 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)s-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-OH
133 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 134 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 135 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)io-CH3 136 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)io-CH3 137 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-B ip(2-Me)-COO-(CH2)6-CH3 138 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-B ip(2-Me)-COO-(CH2)6-CH3 139 CH3-(CH2)lo-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-B ip(2-Me)-COO-(CH2)6-CH3 140 CH3-(CH2)lo-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 141 HA-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
142 H-Aib-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
143 Ha-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
144 H-(N(Me))A-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
145 H-(N(Me))A-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
146 H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
147 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me)-OH
148 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Mc)-OH
149 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-OH
150 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-OH
151 Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-OH

152 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-OH

153 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(1VIe))-Bip(2-Me)-COO-(CH2)6-CH3 154 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 155 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)io-CH3 156 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)io-CH3 157 CH3-(CHa)6-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-B ip(2-Me)-COO-(CHa)6-CH3 158 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-B ip(2-Me)-COO-(CH2)6-CH3 159 CH3-(CH2)io-NH-H-(N(Me))A-(N(Me))-(CH2)s-(N(Me))-Bip(2-Et)-(N(Me))-B ip(2-Me)-COO-(CHa)6-CH3 160 CH3-(CH2)lo-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-B ip(2-Me)-COO-(CH2)6-CH3 Table 9:
S. Sequence No.
1 HA-(CH2)3-DVSSYLEGQAAKEFIKELEKLL
2 HAib-(CH2)3-DVSSYLEGQAAKEFIKELEKLL
3 HAibEGTFTSDVSSYLEGQ-(CH2)2-KELEKLL
4 HAibEGTFTSDVSSYLEGQ-(CH2)3-KELEKLL
HAibEGTFTSDVSSYLE-(CHa)2-FIKELEKLL
6 HAibEGT-(a-Me)Phe(2-F)-TSDVSSYLE-(CH2)2-FIKELEKLL
7 HAib-(CHa)3-VSSYLE-(CH2)Z-FIKELEKLL
8 HAib-(CH2)3-VSSYLE-(CH2)3-FIKELEKLL
9 HAib-(CH2)3-YLE-(CH2)3-FIKELEKLL
HAib-(CH2)4-YLE-(CH2)3-FIKELEKLL
11 HAib-(CH2)4-YL-(CH2)3-FIKELEKLL
12 HAib-(CH2)4-Y-(CH2)3-FIKELEKLL
13 HAib-(CH2)4-FIKELEKLL
14 HAib-(CH2)5-FIKELEKLL
HAib-(CH2)6-FIKELEKLL
16 HAib-(CH2)8-FIKELEKLL
17 HAib-(CH2)3-VSSYLEGQ-(CHa)3-KELEKLL
18 HAib-(CH2)3-VSSYLEG-(CH2)3-KELEKLL

19 HAib-(CH2)3-VSSYLE-(CH2)4-KELEKLL
20 HAib-(CH2)3-SSYLE-(CH2)4-KELEKLL
21 HAib-(CH2)3-SYLE-(CH2)4-KELEKLL
22 HAib-(CH2)3-YLE-(CH2)4-KELEKLL
23 HAib-(CH2)3-YL-(CH2)4-KELEKLL
24 HAib-(CH2)3-Y-(CH2)4-KELEKLL
25 HAib-(CH2)5-KELEKLL
26 HAib-(CH2)6-KELEKLL
27 HAib-(CH2)8-KELEKLL

The peptidomimetics prepared as described above were tested for GLP-1 agonist activity in vitro using the cAMP cell-based assay described below. The mimetic peptide analog stimulated cAMP production in a dose response manner and the corresponding EC50 value were determined for some of the selected peptidomimetics, which are active in vitro at 10 to 100 nM range. The EC50 value of EX-4 was used as a positive control.
Cyclic AMP deterinination The GLP-1 receptor is a G-protein coupled receptor. GLP-1 (7-36)-amide, the biologically active form, binds to the GLP-1 receptor and through signal transduction causes activation of adenylate cyclase and raises intracellular cAMP levels. To monitor agonism of peptide compounds in stimulating the GLP-1 receptor, adenyl cyclase activity was monitored by assaying for cellular cAMP levels.
cAMP assay:
Stably transfected CHO/HGLPIR cells were assayed for cAMP generation in a semi high throughput platform using DiscoverX cAMP kit with Exendin-4 as a positive control. The activity of NCEs was determined as % Exendin-4 activity at 0.01 M
concentration. The positive compounds were further validated for cAMP generation using indirect cAMP ELISA
kit (R & D systems) The activity of the compounds was expressed as finol cAMP/
g of protein.
EC50 values of some of the representative compounds (I to IV) are shown in Figure 1.
Demonstration of in vivo efficacy of compounds:
The in- vivo glucose lowering properties of some of the representative compounds in animal models is -described below. This test was used to examine in vivo efficacy of compounds of the present invention on blood glucose at hyperglycemia. The intra peritoneal glucose tolerance test (IPGTT) was performed in overnight fasted Swiss Albino Mice (SAM), weighing 25-30 g. Mice were given glucose load of 1.5g/

Kg/ 10 ml and blood was collected at different time intervals, via retroorbital plexus.
Test compounds (peptidomimetics) were dissolved in an appropriate vehicle at a concentration in nmol/ ml equivalent to the dose that was to be administered in nmol /
kg, so that each mouse would receive the same volume / weight of dosing solution.
Blood samples were drawn prior to Vehicle/Test compound/Glucose load (0 minute) and then at 15 min, 30 min, 60 min and 120 min. Vehicle/Test compound was administered 15 minutes prior to glucose load, via intra-peritoneal route of administration. Blood samples were centrifuged and the obtained -serum Was stored at -20 C for analysis. Test compounds were examined along with a reference (positive control) and a vehicle control, with n = 6 animals per group. Glucose was determined by the GOD/POD method from serum. The mean value of duplicate results was calculated. The absolute values of glucose in serum levels were calculated using MS Excel software. The 0-minute base line corrected line graph were plotted using Graphpad prism software (ver 3.0). Area under the Curve (AUC) and Base line corrected area under the curve (BCAUC) were calculated and analyzed by performing One way ANOVA
followed by Dunnett's post test using Graphpad prism software (ver 3.0).
- Using above experimental protocol, in vivo glucose lowering properties of some of the selected compounds, which showed in vitro EC50, in CHO-GLP-1R cAMP
assay, in the range of 1-50 nM range were determined. In Table 10, the in vivo glucose lowering potencies (ED50 in IPGTT SAM model) of selected four representative compounds (Comp. I, II, III & IV) were given.
Table 10: In vivo potencies of compound I to IV (ED50), in IPGTT SAM Model Comp. ED50 in IPGTT SAM Model (n = 6) I 1 mole / kg II 500 nM / Kg III 250nM/kg IV 100nM/Kg Several compounds of the present invention were screened in vivo, using other animal models, such as ob/ob, db/db and C57 and they showed in vivo efficacy and potency in varying degrees.
Utilities:
The present invention provides novel GLP-1 peptide mimics, with a preference for mimicking GLP-1, such that the compounds of the present invention have agonist activity for the GLP-1 receptor. Further, many of the GLP peptide mimics of the present invention exhibit increased stability to proteolytic cleavage as compared to GLP-1 native sequences.
Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating or delaying the progression or onset of diabetes (preferably type II, impaired glucose tolerance, insulin resistance and diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts), hyperglycemia, hyperinsulinemia, hypercholesterolemia, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis, hypertension, intestinal diseases (such as necrotizing enteritis, microvillus inclusion disease or celic disease). The compound of the present invention may also be utilized to increase the blood levels of high density lipoprotein (HDL).
In addition, the conditions, diseases collectively referenced to as 'Syndrome X' or metabolic syndrome as detailed in Johannsson J., Clin. Endocrinol. Metab., 82, 727-34,1997, may be treated employing the compounds of the invention. The compounds of the present invention may optionally be used in combination with suitable DPP-IV
inhibitors for the treatment of some of the above disease states either by administering the compounds sequentially or as a formulation containing the compounds of the present invention along with a suitable DPP-IV inhibitors.
No adverse effects were observed for any of the mentioned compounds of invention. The compounds of the present invention showed good glucose serum-lowering activity in the experimental animals used. These compounds are used for the testing/ prophylaxis of diseases caused by hyperinsulinaemia, hyperglycemia such as NIDDM, metabolic disorders and obesity since such diseases are inter-linked to each other.

DEMANDE OU BREVET VOLUMINEUX

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PLUS D'UN TOME.

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VOLUME

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Claims

1. An isolated polypeptide having a sequence of Formula (I), including its tautomers, solvates and pharmaceutically acceptable salts A-X1-S1-Y-S2-X2-B (I) wherein, A represents NH-R1, wherein R1 represents hydrogen, groups selected from linear or branched (C1-C15) alkyl chain, an amino acid or peptide containing one, two or three natural amino acid residues, R3-CO- group, R3O-C(O)- group, a sulfonyl group of formula R3-SO2-, each of these groups may be substituted; R3 is selected from linear or branched (C1-C10) alkyl, (C3-C6) cycloalkyl, aryl, heteroaryl, arylalkyl groups, each of these groups may be substituted;
B represents -COOR2, -CONHR2 or CH2OR2, R2 represents H, groups selected from linear or branched (C1-C10) alkyl, aryl groups selected from phenyl, napthyl, indanyl, fluorenyl, biphenyl groups, aralkyl group, wherein the aryl groups are as defined earlier, each of these groups may be substituted;
each of S1 and S2 may independently be a bond or independently represents a group '-NH-(CH2)n-COO-', where, n=1-9;
Y represents a bond or -CO-, --(CH2)m- (m = 1-3), 'O', 'S', -CO-NH-, -CO-NR4-, or represents a short peptide containing one or two or three amino acids selected from natural or non-natural amino acids; where R4 represents H, optionally substituted groups selected from linear or branched (C1-C10) alkyl or aryl groups selected from phenyl, napthyl, indanyl, fluorenyl, biphenyl groups; with the proviso that when S1-Y-S2 represents a bond, X1 is selected from the following amino acid sequences HAEGTFTSD, HAEGTFTSDV, HAEGTFTSDVS, HAEGTFTSDVSS, HAEGTFTSDVSSY, HAEGTFTSDVSSYL, HAEGTFTSDVSSYLE, HAEGTFTSDVSSYLEG, HAEGTFTSDVSSYLEGQ, HAEGTFTSDVSSYLEGQA, HAEGTFTSDVSSYLEGQAA, HAEGTFTSDVSSYLEGQAAK, HAEGTFTSDVSSYLEGQAAKE, HAEGTFTSDVSSYLEGQAAKEF, HAEGTFTSDVSSYLEGQAAKEFI, with the further option that one or more of these amino acids may be replaced by unnatural amino acids, and X2 is selected from the following amino acid sequences GPSSGAPPPS or KELEKLL or GPPS or VKGR;
and when S1-Y-S2 does not represent a bond X1 is selected from the following amino acid sequences HA, HAE, HAEG, HAEGT, HAEGTF, HAEGTFT, HAEGTFTS, HAEGTFTSD with the further option that one or more of these amino acids may be replaced by unnatural amino acids;
X2 is selected from GPSSGAPPPS or KELEKLL or GPPS or VKGR or a dipeptide, selected from combination of two amino acids consisting of natural or unnatural amino acids, having a side chain containing an arylalkyl or heterorylalkyl moieties selected from benzyl, napthylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, isooxazolylmethyl, quinolylmethyl, benzofuranylmethyl, benzothienylmethyl, indolinylmethyl, indolylmethyl, dibenzofuranylmethyl, dibenzothienylmethyl, benzodihydrofuranylmethyl, benzodihydrothienylmethyl, thienopyrimidylmethyl, benzimidazolylmethyl, phenanthrenylmethyl, dihydrophenanthrenylmethyl, fluorenylmethyl, dibenzofuranylmethyl, dibenzothiophenyl methyl groups, where each of these groups may be optionally substituted with (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo, hydroxy or optionally substituted aryl or heteroaryl groups, with the further provision that such aryl or heteroaryl substituents may further be optionally substituted with (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo, hydroxy or aryl or heteroaryl groups.

2. A compound as claimed in claim 1 wherein the non-natural amino acids are represented by the general formula (IIa) wherein R5 is selected from H, F, (C1-C5) alkyl, the stereochemical configuration at the carbon bearing R5 may be (R) or (S); R6 is selected from H or (C1-C3) alkyl; each of R7 and R8 is independently selected from H, (C1-C2) alkyl or halogen atom, preferably fluorine atom; R9 represents groups, selected from (C1-C5) alkyl, aryl or heteroryl moieties selected from phenyl, napthyl, pyridyl, thienyl, furyl, imidazolyl, isooxazolyl, quinolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, dibenzofuranyl, dibenzothienyl, benzodihydrofuranyl, benzodihydrothienyl, thienopyrimidyl, benzimidazolyl, phenanthrenyl, dihydrophenanthrenyl, fluorenyl, dibenzofuranyl, dibenzothiophenyl groups, where each of these groups may be optionally substituted with (C1-C6) alkyl, (C1-C6) alkoxy, cyano, halo, hydroxy or optionally substituted aryl or heteroaryl groups, with the further provision that such aryl or heteroaryl substituents may further be optionally substituted with (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halo, hydroxy or aryl or heteroaryl groups.

3. The isolated peptide as claimed in claim 1, wherein the dipeptide representing X2 is preferably selected from Bip, Bip(2-Me), Bip(2-Et), Bip(2-Ipr), Bip(2-CN), Bip(2'-Et-4'-OMe), Bip(4'-fluoro), Bip(4'-Phenyl), 2-(9,10-Dihydro-phenanthrenyl]-Ala, 2-(Phenanthrenyl)-Ala, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Fluorenyl-Ala,

4-dibenzofuran-Phe, 4-dibenzothiophene-Phe, 4-(2'-methylphenyl)-3-pyridylalanine groups.

4. The isolated peptide as claimed in claim 1, wherein the substituents are selected from hydroxyl, oxo, halo, thio, nitro, amino, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, carboxylic acid and its derivatives selected from esters and amides.

5. The isolated polypeptide of claim 1, wherein the isolated polypeptide is a compound selected from HGEGTFTSD-(CH2)3-GPSSGAPPPS
HGEGTFTSD-(CH2)4-GPSSGAPPPS
HGEGTFTSD-(CH2)5-GPSSGAPPPS
HGEGTFTSD-(CH2)6-GPSSGAPPPS
HGEGTFTSD-(CH2)7-GPSSGAPPPS

HGEGTFTSD-(CH2)10-GPSSGAPPPS
HGEGTFTSD-(CH2)11-GPSSGAPPPS
HGEGTFTSDLSKQM-(CH2)3-GPSS
HGEGTFTSDLSKQM-(CH2)4-GPSS
HGEGTFTSDLSKQM-(CH2)5-GPSS
HGEGTFTSDLSKQM-(CH2)6-GPSS
HGEGTFTSDLSKQM-(CH2)7-GPSS
HGEGTFTSDLSKQM-(CH2)10-GPSS
HGEGTFTSDLSKQM-(CH2)11-GPSS
HGEGTFTSDLSKQME-G-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)2-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)3-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)4-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)5-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)6-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)7-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)10-GPSSGAPPPS
HGEGTFTSDLSKQME-(CH2)11-GPSSGAPPPS
HAEGTFTSD-(CH2)2-VKGR
HAEGTFTSD-(CH2)3-VKGR
HAEGTFTSD-(CH2)4-VKGR
HAEGTFTSD-(CH2)5-VKGR
HAEGTFTSD-(CH2)6-VKGR
HAEGTFTSD-(CH2)10-VKGR
HAibEGTFTSD-(CH2)2-VKGR
HAibEGTFTSD-(CH2)3-VKGR
HAibEGTFTSD-(CH2)4-VKGR
HAibEGTFTSD-(CH2)5-VKGR
HAibEGTFTSD-(CH2)6-VKGR
HAibEGTFTSD-(CH2)10-VKGR
HGEGTFTSDLSKQMKELEKLL
HAEGTFTSDKELEKLL
HGEGTFTSDKELEKLL
HAibEGTFTSDGKELEKLL

HGEGTFTSDGKELEKLL
HGEGTFTSDVSKELEKLL
HAEGTFTSDVSKELEKLL
HAEGTFTSDVSEKELEKLL
HAEGTFTSDVSGKELEKLL
HAEGTFTSDVSSYLEKELEKLL
HAEGTFTSDVSSYLEGKELEKLL
HGEGTFTSDVSSYLEGKELEKLL
HaEGTFTSDVSSYLEGKELEKLL
HAibEGTFTSDVSSYLEGKELEKLL
HAEGTFTSDVSSYLEGKELEKLLVKG
HAEGTFTSDVSSYLEPKELEKLL
HAEGTFTSDVSSYLEGQAAKELEKLL
HAEGTFTSDVSSYLEGQAAKEFIKELEKLL
HAibEGTFTSDVSSYLEGQAAKEFIKELEKLL
HAibEGT-(.alpha.-Me)Phe(2-F)-TSDVSSYLEGQAAKEFIKELEKLL
Des-amino-HAibEGT-(.alpha.-Me)Phe(2-F)-TSDVSSYLEGQAAKEFIKELEKLL
HAEGTFTSD-(CH2)3-KELEKLL
HAEGTFTSD-(CH2)4-KELEKLL
HAEGTFTSD-(CH2)5-KELEKLL
HAEGTFTSD-(CH2)6-KELEKLL
HA-(CH2)3-DVSSYLEGQAAKEFIKELEKLL
HAib-(CH2)3-DVSSYLEGQAAKEFIKELEKLL
HAibEGTFTSDVSSYLEGQ-(CH2)2-KELEKLL
HAibEGTFTSDVSSYLEGQ-(CH2)3-KELEKLL
HAibEGTFTSDVSSYLE-(CH2)2-FIKELEKLL
HGEGTFTSD-(CH2)3-Bip-Bip HAibEGTFTSD-(CH2)3-Bip-Bip HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)3-Bip-Bip HAEGTFTSD-G-Bip(2-Me)-Bip(2-Me) HAibEGTFTSD-G-Bip(2-Me)-Bip(2-Me) HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-Me)-Bip(2-Me) HAEGTFTS-G-Bip(2-Me)-Bip(2-Me) HAibEGTFTS-G-Bip(2-Me)-Bip(2-Me) HAibEGT-((.alpha.-Me)-Phe(2-F)-TS-G-Bip(2-Me)-Bip(2-Me) HAEGTFTS-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGTFTS-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)2-Bip(2-Me)-Bip(2-Me) HAEGTFT-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGTFT-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGT-(.alpha.-Me)-Phe(2-F)-T-(CH2)2-Bip(2-Me)-Bip(2-Me) HAEGTF-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGTF-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGT-(.alpha.-Me)-Phe(2-F)-(CH2)2-Bip(2-Me)-Bip(2-Me) HAEGT-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGT-(CH2)2-Bip(2-Me)-Bip(2-Me) HAEG-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEG-(CH2)2-Bip(2-Me)-Bip(2-Me) HAEGTFTSD-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGTFTSD-(CH2)2-Bip(2-Me)-Bip(2-Me) HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)2-Bip(2-Me)-Bip(2-Me) HAEGTFTSD-G-Bip-Bip(2-Me) HAibEGTFTSD-G-Bip-Bip(2-Me) HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip-Bip(2-Me) HAEGTFTSD-G-Bip(2-Me)-Bip HAibEGTFTSD-G-Bip(2-Me)-Bip HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-Me)-Bip HAEGTFTSD-G-Bip-Bip-HAibEGTFTSD-G-Bip-Bip HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip-Bip HAEGTFTSD-G-Bip-Bip(2-Et) HAibEGTFTSD-G-Bip-Bip(2-Et) HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip-Bip(2-Et) HAEGTFTSD-G-Bip(2-Et)-Bip(2-Et) HAibEGTFTSD-G-Bip(2-Et)-Bip(2-Et) HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-Et)-Bip(2-Et) HAEGTFTSD-G-Bip(2-Et)-Bip HAibEGTFTSD-G-Bip(2-Et)-Bip HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-Et)-Bip HAEGTFTSD-G-Bip(2-Et)-Bip(2-Me) HAibEGTFTSD-G-Bip(2-Et)-Bip(2-Me) HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-Et)-Bip(2-Me) HAEGTFTSD-G-Bip(2-Me)-Bip(2-Et) HAibEGTFTSD-G-Bip(2-Me)-Bip(2-Et) HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-Me)-Bip(2-Et) HGEGTFTSD-G-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-Me)-Bip(2-Me) HGEGTFTSD-G-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-Et)-Bip(2-Et) HGEGTFTSD-(CH2)3-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)3-Bip(2-Me)-Bip(2-Me) HGEGTFTSD-(CH2)4-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)4-Bip(2-Me)-Bip(2-Me) HGEGTFTSD-(CH2)5-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)5-Bip(2-Me)-Bip(2-Me) HGEGTFTSD-(CH2)6-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)6-Bip(2-Me)-Bip(2-Me) HGEGTFTSD-(CH2)10-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)10-Bip(2-Me)-Bip(2-Me) HGEGTFTSD-(CH2)3-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)3-Bip(2-Et)-Bip(2-Et) HGEGTFTSD-(CH2)4-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)4-Bip(2-Et)-Bip(2-Et) HGEGTFTSD-(CH2)5-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)5-Bip(2-Et)-Bip(2-Et) HGEGTFTSD-(CH2)6-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)6-Bip(2-Et)-Bip(2-Et) HGEGTFTSD-(CH2)10-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)10-Bip(2-Et)-Bip(2-Et) HGEGTFTSD-(CH2)11-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)11-Bip(2-Et)-Bip(2-Et) HGEGTFTS-(CH2)3-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)3-Bip(2-Me)-Bip(2-Me) HGEGTFTS-(CH2)4-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)4-Bip(2-Me)-Bip(2-Me) HGEGTFTS-(CH2)5-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)5-Bip(2-Me)-Bip(2-Me) HGEGTFTS-(CH2)6-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)6-Bip(2-Me)-Bip(2-Me) HGEGTFTS-(CH2)10-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)10-Bip(2-Me)-Bip(2-Me) HGEGTFTS-(CH2)11-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)11-Bip(2-Me)-Bip(2-Me) HGEGTFTS-(CH2)3-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)3-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)4-Bip(2-Et)-Bip(2-Et) HGEGTFTS-(CH2)4-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)4-Bip(2-Et)-Bip(2-Et) HGEGTFTS-(CH2)5-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)5-Bip(2-Et)-Bip(2-Et) HGEGTFTS-(CH2)6-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)6-Bip(2-Et)-Bip(2-Et) HGEGTFTS-(CH2)10-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)10-Bip(2-Et)-Bip(2-Et) HGEGTFTS-(CH2)11-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)11-Bip(2-Et)-Bip(2-Et) HGEGTFTS-(CH2)2-Bip(2-Me)-Bip(2-Me) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)2-Bip(2-Me)-Bip(2-Me) HGEGTFTS-(CH2)2-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)2-Bip(2-Et)-Bip(2-Et) HAEGTFTS-(CH2)2-Bip(2-Et)-Bip(2-Et) HAibEGTFTS-(CH2)2-Bip(2-Et)-Bip(2-Et) HAibEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)2-Bip(2-Et)-Bip(2-Et) HGEGTFTSD-(CH2)2-Bip(2-Et)-Bip(2-Et) HGEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)2-Bip(2-Et)-Bip(2-Et) HAEGTFTSD-(CH2)2-Bip(2-Et)-Bip(2-Et) HAibEGTFTSD-(CH2)2-Bip(2-Et)-Bip(2-Et) HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)2-Bip(2-Et)-Bip(2-Et) HAEGTF-(CH2)2-Bip(2-Me)-Bip(2-Et) HAibEGTF-(CH2)2-Bip(2-Me)-Bip(2-Et) HAibEGT-(.alpha.-Me)-Phe(2-F)-(CH2)2-Bip(2-Me)-Bip(2-Et) HAEGTFTSD-G-TrPh-TrPh HAibEGTFTSD-G-TrPh-TrPh HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-TrPh-TrPh HAibEGT-(.alpha.-Me)-Phe(2-F)-(CH2)2-TrPh-TrPh HAibEG-(CH2)2-TrPh-TrPh HAibE-(CH2)2-TrPh-TrPh HAib-(CH2)3-TrPh-TrPh HAEGTFTSD-G-Nap-Nap HAibEGTFTSD-G-Nap-Nap HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Nap-Nap HAEGTFTSD-G-Bip(2-F)-Bip(2-F) HAibEGTFTSD-G-B ip(2-F)-Bip(2-F) AibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2-F)-Bip(2-F) HAEGTFTSD-G-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGTFTSD-G-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-G-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAEGTFTSD-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGTFTSD-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGT-(.alpha.-Me)-Phe(2-F)-TSD-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAEGTFTS-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGTFTS-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGT-(.alpha.-Me)-Phe(2-F)-TS-(CH2)2-Bip(2'-Et-4'-Ome)-4-(2'-Me-Ph)-3-Pyr-Ala HAEGTFT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGTFT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGT-(.alpha.-Me)-Phe(2-F)-T-(CH2).alpha.-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAEGTF-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGTF-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGT-(.alpha.-Me)-Phe(2-F)-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAEG-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAibEG-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala HAEGT-(CH2)2-Bip(2-Me)-Bip(2-Me) HGEGT-(CH2)3-Bip(2-Me)-Bip(2-Me) HGEGT-(CH2)4-Bip(2-Me)-Bip(2-Me) HGEGT-(CH2)5-Bip(2-Me)-Bip(2-Me) HGEGT-(CH2)6-Bip(2-Me)-Bip(2-Me) HAEGT-(CH2)2-Bip(2-Me)-DBip(2-Me) HAEGT-(CH2)2-DBip(2-Me)-Bip(2-Me) HaEGT-(CH2)2-Bip(2-Me)-Bip(2-Me) HGEG-(CH2)3-Bip(2-Me)-Bip(2-Me) HAEG-(CH2)3-Bip(2-Me)-Bip(2-Me) HGEG-(CH2)4-Bip(2-Me)-Bip(2-Me) HGEG-(CH2)5-Bip(2-Me)-Bip(2-Me) HGEG-(CH2)6-Bip(2-Me)-Bip(2-Me) HAEG-(CH2)3-Bip(2-Et)-Bip(2-Me) HAEG-(CH2)3-Bip(2-Me)-DBip(2-Me) HAEG-(CH2)4-Bip(2-Me)-DBip(2-Me) HAEG-(CH2)5-Bip(2-Me)-DBip(2-Me) HGEG-(CH2)5-DBip(2-Me)-Bip(2-Me) HAE-(CH2)3-Bip(2-Me)-Bip(2-Me) HAE-(CH2)3-Bip(2-Me)-DBip(2-Me) HAE-(CH2)2-D-Bip(2-Me)-Bip(2-Me) HAE-(CH2)3-D-Bip(2-Me)-Bip(2-Me) HAE-(CH2)4-D-Bip(2-Me)-Bip(2-Me) HAE-(CH2)4-Bip(2-Me)-DBip(2-Me) HAE-(CH2)5-D-Bip(2-Me)-Bip(2-Me) HAE-(CH2)3-Bip(2-Et)-Bip(2-Me) HAE-(CH2)2-Bip(2-Me)-Bip(2-Me) H-(CH2)3-Bip(2-Me)-Bip(2-Me) H-(CH2)4-Bip(2-Me)-Bip(2-Me) H-(CH2)5-Bip(2-Me)-Bip(2-Me) H-(CH2)3-Bip(2-Et)-Bip(2-Me) H-(CH2)4-Bip(2-Et)-Bip(2-Me) H-(CH2)5-Bip(2-Et)-Bip(2-Me) H-(CH2)6-Bip(2-Et)-Bip(2-Me) H-(CH2)10-Bip(2-Et)-Bip(2-Me) H-(CH2)5-Bip(2-Me)-DBip(2-Me) H-(CH2)5-DBip(2-Me)-Bip(2-Me) H-(CH2)5-DBip(2-Me)-DBip(2-Me) HG-(CH2)3-Bip(2-Me)-Bip(2-Me) HG-(CH2)4-Bip(2-Me)-Bip(2-Me) HG-(CH2)3-Bip(2-Et)-Bip(2-Me) HG-(CH2)4-Bip(2-Et)-Bip(2-Me) HG-(CH2)3-Bip(2-Et)-DBip(2-Me) HG-(CH2)3-Bip(2-Me)-DBip(2-Me) FA-(CH2)3-DBip(2-Me)-Bip(2-Et) FA-(CH2)3-DBip-Dbip Ha-(CH2)3-Bip(2-Me)-Bip(2-Me) Ha-(CH2)4-Bip(2-Me)-Bip(2-Me) Ha-(CH2)5-Bip(2-Me)-Bip(2-Me) Ha-(CH2)3-Bip(2-Et)-Bip(2-Me) Ha-(CH2)3-Bip(2-Et)-DBip(2-Me) Ha-(CH2)3-Bip(2-Me)-DBip(2-Me) Ha-(CH2)3-Bip(2-Et)-DBip(2-Et) Ha-(CH2)3-Bip(2-Me)-Bip Ha-(CH2)3-(N(Me))-DBip(2-Me)-Bip(2-Et) Ha-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me) Ha-(CH2)3-(N(Me))-DBip-Bip(2-Et) Ha-(CH2)3-DBip(2-Me)-Bip(2-Et) HA-(CH2)3-Bip(2-Me)-Bip(2-Me) HA-(CH2)4-Bip(2-Me)-Bip(2-Me) HA-(CH2)5-Bip(2-Me)-Bip(2-Me) HA-(CH2)6-Bip(2-Me)-Bip(2-Me) HA-(CH2)10-Bip(2-Me)-Bip(2-Me) HA-(CH2)11-Bip(2-Me)-Bip(2-Me) HA-(CH2)3-Bip(2-Et)-Bip(2-Me) HA-(CH2)3-Bip(2-Et)-DBip(2-Et) HA-(CH2)3-DBip(2-Me)-DBip(2-Me) HA-(CH2)3-DBip(2-Me)-Bip(2-Me) HA-(CH2)3-Bip(2-Me)-DBip(2-Me) HA-(CH2)3-Bip(2-Ipr)-Bip(2-Ipr) HA-(CH2)3-Bip(2-Ipr)-Bip(2-Me) HA-(CH2)3-Bip(2-Me)-Bip(2-Ipr) HA-(CH2)4-Bip(2-Et)-Bip(2-Me) HA-(CH2)3-Bip(2-Me)-DBip(2-Et) HA-(CH2)2-Bip(2-Et)-Bip(2-Me) HA-(CH2)5-Bip(2-Et)-Bip(2-Me) HA-(CH2)6-Bip(2-Et)-Bip(2-Me) HA-(CH2)2-Bip(2-Me)-Bip(2-Me) HA-(CH2)3-DBip(2-Et)-DBip(2-Me) HA-(CH2)3-DBip(2-Et)-Bip(2-Me) HA-(CH2)2-Bip(2-Me)-DBip(2-Me) HA-(CH2)3-Bip(2-Et)-Bip(2-Et) HA-(CH2)3-DBip(2-Et)-DBip(2-Et) HA-(CH2)3-DBip(2-Et)-Bip(2-Et) HA-(CH2)3-DBip(2-Me)-DBip(2-Et) HA-(CH2)3-Bip(2-Me)-Bip(2-Et) HA-(CH2)3-DBip(2-Me)-Bip(2-Et) HA-(CH2)3-Bip-Bip HA-(CH2)3-Bip-D-Bip HA-(CH2)3-DBip-D-Bip HA-(CH2)3-DBip-Bip HA-(CH2)3-Bip-Bip(2-Me) HA-(CH2)3-Bip(2-Me)-Bip HA-(CH2)3-Bip(2-Et)-Bip HA-(CH2)3-Bip-Bip(2-Et) HA-(CH2)3-Bip(2-Ipr)-DBip(2-Ipr) HA-(CH2)3-DBip(2-Ipr)-Bip(2-Ipr) HA-(CH2)3-DBip(2-Ipr)-DBip(2-Ipr) HA-(CH2)3-Bip(2-Me)-Bip(2-CN) HA-(CH2)3-Bip-Bip(2-CN) HA-(CH2)3-Bip(2-Et)-Bip(2-CN) HA-(CH2)3-Bip(2-Ipr)-Bip(2-CN) HA-(CH2)3-Bip(2-CN)-Bip(2-Me) HA-(CH2)3-Bip(2-CN)-Bip HA-(CH2)3-Bip(2-CN)-Bip(2-Et) HA-(CH2)3-Bip(2-CN)-Bip(2-Ipr) HA-(CH2)3-Bip(2-CN)-Bip(2-CN) HA-(CH2)2-F-(CH2)2-Bip(2-Et)-DBip(2-Et) HA-(CH2)2-F-(CH2)2-Bip(2-Et)-DBip(2-Me) HA-(CH2)5-Bip(2-Me)-DBip HA-(CH2)3-Bip(2-Me)-DBip-R
HA-(CH2)3-DBip(2-Me)-DBip HA-(CH2)5-Bip(2-Me)-DBip(2-Me) HA-(CH2)5-DBip(2-Me)-Bip(2-Me) HA-(CH2)4-D(Bip)-Bip(2-Et) HA-(CH2)5-D(Bip)-Bip(2-Et) HA-(CH2)4-Bip(2-Me)-DBip(2-Me) HA-(CH2)5-Bip(2-Me)-DBip(2-Me) HA-(CH2)3-(N(Me))-DBip-Bip(2-Et) HA-(CH2)4-DBip(2-Me)-Bip(2-Et) HA-(CH2)5-DBip(2-Me)-Bip(2-Et) HA-(CH2)3-(N(Me))-DBip(2-Me)-Bip(2-Et) HA-(CH2)4-Bip(2-Me)-DBip HA-(CH2)5-Bip(2-Me)-DBip HA-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me) HA-(N(Me))-(CH2)3-DBip(2-Me)-Bip(2-Et) HA-(N(Me))-(CH2)3-DBip-Bip(2-Et) HA-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me) HA-(N(Me))-(CH2)3-Bip(2-Me)-DBip HAE-(CH2)2-F-(CH2)2-Bip(2-Et)-DBip(2-Et) HAE-(CH2)2-F-(CH2)2-Bip(2-Et)-DBip(2-Me) HAib-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me)

6. The isolated polypeptide of claim 1 wherein the isolated polypeptide is a compound selected from HA-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-Aib-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Ha-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip (2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)6-NH-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 HA-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-Aib-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Ha-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-B ip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 HA-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-Aib-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-a-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-(N (Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH=H-N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 HAE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-Aib-E-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 HaE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AE-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-E-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala NH-(CH2)6-CH3 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3 -Pyr-Ala-NH-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)6-NH-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 HAEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-Aib-EG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 HaEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AEG-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)6-NH-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 HAEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-Aib-EGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 HaEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AEGT-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 Des-amino-H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr- Ala-NH2 Des-amino-H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH2 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)6-NH-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-NH-(CH2)6-CH3 HA-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 H-Aib-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 Ha-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 H-(N(Me))A-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 H-(N(Me))A-(N(Me))-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2-Me)-Bip(2-Me)-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-Bip(2-Me)-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-Bip(2-Me)-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH2 Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)10-CH3 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 HA-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 H-Aib-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 Ha-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 H-(N(Me))A-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 H-(N(Me))A-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me)-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me)-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me)-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH2 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH2 Des-amino-H-(N(Me))A-(N(Me))-(CH2))3-(N(Me))-Rip(2-Et)-(N(Me))-Rip(2-Me)-Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH2 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)10-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)10-CH3 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-NH-(CH2)6-CH3 HA-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-Aib-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Ha-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
'H-(N(Me))A-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)6-NH-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))A-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))Aib-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 HA-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-Aib-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Ha-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 HA-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-Aib-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Ha-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)4-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))A-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-H-N(Me))Aib-(N(Me))-(CH2)4-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 HAE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-Aib-E-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
HaE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AE-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AE-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-E-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 H-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)6-NH-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))AE-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))Aib-E-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 HAEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-Aib-EG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
HaEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEG-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEG-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-EG-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 H-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)6-NH-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))AEG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))Aib-EG-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 HAEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-Aib-EGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
HaEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEGT-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEGT-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
Des-amino-H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-OH
H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 H-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 H-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)10-CH3 CH3-(CH2)6-NH-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)6-NH-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))AEGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 CH3-(CH2)10-NH-(N(Me))Aib-EGT-(N(Me))-(CH2)2-(N(Me))-Bip(2'-Et-4'-OMe)-(N(Me))-4-(2'-Me-Ph)-3-Pyr-Ala-COO-(CH2)6-CH3 HA-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
H-Aib-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
Ha-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
H-(N(Me))A-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
H-(N(Me))A-(N(Me))-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2-Me)-Bip(2-Me)-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-Bip(2-Me)-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-Bip(2-Me)-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-OH
Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-OH
Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)10-CH3 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Me)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 HA-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
H-Aib-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
Ha-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
H-(N(Me))A-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
H-(N(Me))A-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-Bip(2-Et)-Bip(2-Me)-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me)-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-Bip(2-Me)-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-OH
H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-OH
Des-amino-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-OH
Des-amino-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-OH
H-(N(Me))A-(N(Me))-(CH2)3-(N(Mc))-Bip(2-Et)-(N(Mc))-Bip(2-Mc)-COO-(CH2)6-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)10-CH3 H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)10-CH3 CH3-(CH2)6-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 CH3-(CH2)6-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))A-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 CH3-(CH2)10-NH-H-(N(Me))Aib-(N(Me))-(CH2)3-(N(Me))-Bip(2-Et)-(N(Me))-Bip(2-Me)-COO-(CH2)6-CH3 HA-(CH2)3-DVSSYLEGQAAKEFIKELEKLL
HAib-(CH2)3-DVSSYLEGQAAKEFIKELEKLL
HAibEGTFTSDVSSYLEGQ-(CH2)2-KELEKLL
HAibEGTFTSDVSSYLEGQ-(CH2)3-KELEKLL
HAibEGTFTSDVSSYLE-(CH2)2-FIKELEKLL
HAibEGT-(.alpha.-Me)Phe(2-F)-TSDVSSYLE-(CH2)2-FIKELEKLL
HAib-(CH2)3-VSSYLE-(CH2)2-FIKELEKLL
HAib-(CH2)3-VSSYLE-(CH2)3-FIKELEKLL
HAib-(CH2)3-YLE-(CH2)3-FIKELEKLL
HAib-(CH2)4-YLE-(CH2)3-FIKELEKLL
HAib-(CH2)4-YL-(CH2)3-FIKELEKLL
HAib-(CH2)4-y-(CH2)3-FIKELEKLL
HAib-(CH2)4-FIKELEKLL
HAib-(CH2)5-FIKELEKLL
HAib-(CH2)6-FIKELEKLL
HAib-(CH2)8-FIKELEKLL
HAib-(CH2)3-VSSYLEGQ-(CH2)3-KELEKLL
HAib-(CH2)3-VSSYLEG-(CH2)3-KELEKLL
HAib-(CH2)3-VSSYLE-(CH2)4-KELEKLL
HAib-(CH2)3-SSYLE-(CH2)4-KELEKLL
HAib-(CH2)3-SYLE-(CH2)4-KELEKLL
HAib-(CH2)3-YLE-(CH2)4-KELEKLL
HAib-(CH2)3-YL-(CH2)4-KELEKLL
HAib-(CH2)3-Y-(CH2)4-KELEKLL
HAib-(CH2)5-KELEKLL
HAib-(CH2)6-KELEKLL
HAib-(CH2)8-KELEKLL

7. A pharmaceutical composition comprising compounds as claimed in claims 1-6 prepared according to the processes described herein and a suitable pharmaceutically acceptable carrier(s).

8. The compounds or their pharmaceutical compositions as claimed in claims 1-7, which possess the ability to mimic the biological activity of GLP-1, more preferably mimic the GLP-1R agonist activity.

9. The compounds or their pharmaceutical compositions as claimed in any of the claims 1-7, useful for the treatment or prevention of diseases wherein GLP-1R
peptide plays a patho-physiological function.

10. A method of preventing or treating diseases caused by hyperlipidaemia, hypercholesteremia, hyperglycemia, hyperinsulinemia, elevated blood levels of free fatty acids or glycerol, hypertriglyceridemia, wound healing, obesity, impaired glucose tolerance, leptin resistance, insulin resistance, diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts, comprising administering an effective, non-toxic amount of compound of formula (I) as defined in any preceding claims to a patient in need thereof.

11. The method according to any preceding claims, wherein the disease is type diabetes, impaired glucose tolerance, dyslipidaemia, hypertension, obesity, atherosclerosis, hyperlipidaemia, coronary artery disease, cardiovascular disorders and other diseases wherein insulin resistance is the underlying pathophysiological mechanism.

12. A medicine for treating/reducing any of the disease conditions described in any preceding claims which comprises administering a compound of formula (I), as defined in claims 1-7 and a pharmaceutically acceptable carrier, diluent, excipients or solvate to a patient in need thereof.

13. A medicine for treating/reducing any of the disease conditions described in any preceding claims which comprises administering a compound of formula (I), as defined in claims 1-7 in combination with a suitable DPP IV inhibitor, to a patient in need thereof.

14. Use of compounds of formula (I), alone or in combination with suitable DPP
IV
inhibitors, their pharmaceutical compositions and medicines containing them as defined in any previous claims as a medicament suitable for the treatment of diseases mentioned in any of the aforesaid claims.