AU2006225176A1

AU2006225176A1 - Novel exendin agonist compounds

Info

Publication number: AU2006225176A1
Application number: AU2006225176A
Authority: AU
Inventors: Nigel Robert Arnold Beeley; Kathryn S Prickettt
Original assignee: Amylin Pharmaceuticals LLC
Current assignee: Amylin Pharmaceuticals LLC; AstraZeneca Pharmaceuticals LP
Priority date: 1997-11-14
Filing date: 2006-09-29
Publication date: 2006-10-26
Anticipated expiration: 2018-11-13
Also published as: AU2006225176B2

Description

S&F Ref: 506660D2

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant Actual Inventor(s): Address for Service: Invention Title: Amylin Pharmaceuticals, Inc., of 9373 Towne Centre Drive, San Diego, California, 92121, United States of America Nigel Robert Arnold Beeley, Kathryn S Prickett Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Novel exendin agonist compounds The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c

\O

O1

SDESCRIPTION

C NOVEL EXENDIN AGONIST COMPOUNDS

\O

In

(O

c\ Field of the Inventin The present invention relates to novel compounds which S have activity as exendin agonists. These compounds are useful in the preparation of medicaments for treatment of Type I and II diabetes, in treatment of disorders which would be benefited by agents which lower plasma glucose levels and in treatment of disorders which would be benefited [C with agents useful in delaying and/or slowing gastric emptying.

BACKGROUND

The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art to the presently claimed invention, nor that any of the publications specifically or implicitly referenced are prior art to that invention.

Exendin The exendins are peptides that are found in the venom of Z0 the Gila-monster, a lizard endogenous to Arizona and Northern Mexico. Exendin-3 [SEQ. ID. NO. 11 is present in the venom of Heloderma horridum, and exendin-4 [SEQ. ID. NO. 2] is present in the venom of Heloderma suspectum (Eng, et al., J. Biol.

Chem., 265:20259-62, 1990; Eng., et al., J. Biol. Chem., 267:7402-05, 1992). The amino acid sequence of exendin-3 is shown in Figure 1. The amino acid sequence of exendin-4 is shown in Figure 2. The exendins have some sequence similarity to several members of the glucagon-like peptide family, with the highest homology, 53%, being to GLP-1[7-36]NH, [SEQ. ID. NO. 3] (Goke, et al., J. Biol. Chem., 268:19650-55, 1993).

GLP-1[7-36]NH,, also known as proglucagon[78-107] or simply "GLP-1" as used most often herein, has an insulinotropic effect, stimulating insulin secretion from pancreatic P-cells; GLP-1 also inhibits glucagon secretion from pancreatic a-cells (Orsov, et al., Diabetes, 42:658-61, 1993; D'Alessio, et al., J_ Clin. Invest., 97:133-38, 1996). The amino acid sequence of GLP-l is shown in Figure 3. GLP-l is reported to inhibit gastric emptying (Willms B, et al., J Clin Endocrinol Metab 81 327-32, 1996; Wettergren A, et al., DiQ Dis Sci 38 665-73, 1993), and gastric acid secretion. Schjoldager BT, et 2o al., Dig Dis Sci 34 703-8, 1989; O'Halloran DJ, et al., J Endocrinol 126 169-73, 1990; Wettergren A, et al., Dig Dis Sci 38 665-73, 1993). GLP-1[7-37], which has an additional glycine residue at its carboxy terminus, also stimulates insulin secretion in humans (Orsov, et al., Diabetes, 42:658-61, 1993).

A transmembrane G-protein adenylate-cyclase-coupled receptor believed to be responsible for the insulinotropic effect of GLP-l has been cloned from a P-cell line (Thorens, Proc. Natl.

Acad. Sci. USA 89:8641-45, 1992), hereinafter referred to as the "cloned GLP-1 receptor." Exendin-4 reportedly acts at GLP-1 receptors on insulin-secreting PTC1 cells, at dispersed acinar cells from guinea pig pancreas, and at parietal cells from stomach; the peptide is also reported to stimulate somatostatin release and inhibit gastrin release in isolated stomachs (Goke, et al., J. Biol. Chem. 268:19650-55, 1993; Schepp, et al., Eur.

J. Pharmacol., 69:183-91, 1994; Eissele, et al., Life Sci., 55:629-34, 1994). Exendin-3 and exendin-4 were reportedly found to stimulate cAMP production in, and amylase release from, pancreatic acinar cells (Malhotra, et al., Regulatory (O Peptides,41:149-56, 1992; Raufman, et al., J. Biol. Chem.

267:21432-37, 1992; Singh, et al., Regul. Pept. 53:47-59, 1994).

Based on their insulinotropic activities, the use of exendin-3 and exendin-4 for the treatment of diabetes mellitus and the prevention of hyperglycemia has been proposed (Eng, U.S. Patent No. 5,424,286).

Agents which serve to delay gastric empying nave found a place in medicine as diagnostic aids 4n gastro-intestinal radiologic examinations. For example, ilucagon is a polypeptide hormone which is produced by the a cells of the pancreatic .0 islets of Langerhans. It is a hyperglycemic agent which mobilizes glucose by activating hepatic glycogenolysis. It can to a lesser extent stimulate the secretion of pancreatic insulin. Glucagon is used in the treatment of insulin-induced hypoglycemia, for example, when administration of glucose intravenously is not possible. However, as glucagon reduces the motility of the gastro-intestinal tract it is also used as a diagnostic aid in gastro-intestinal radiological examinations.

Glucagon has also been used in several studies to treat various painful gastro-intestinal disorders associated with spasm.

Daniel, et al. (Br. Med. 3:720, 1974) reported quicker symptomatic relief of acute diverticulitis in patients treated with glucagon compared with those who had been treated with analgesics or antispasmodics. A review by Glauser, et al. (J.

Am. Coll. Emergency Physns, 8:228, 1979) described relief of acute esophageal food obstruction following glucagon therapy.

In another study, glucagon significantly relieved pain and tenderness in 21 patients with biliary tract disease compared with 22 patients treated with placebo Stower, et al., Br.

(0 J. Surg., 69:591-2, 1982).

Methods for regulating gastrointestinal motility using amylin agonists are described in International Application No.

PCT/US94/10225, published March 16, 1995.

Methods for regulating gastrointestinal motility using 1/ exendin agonists are described in PCT/US 97/14199 (WO 98/05351).

Methods for reducing food intake using exendin agonists are described in U.S. Patent Application Serial No. 09/003,869, published as PCT/98/00449,entitled "Use of Exendin and Agonists Thereof for the Reduction of Food Intake".

Novel exendin agonist compounds are described in PCT Application Serial No. PCT/US98/16387 filed August 6, 1998, entitled "Novel Exendin Agonist Compounds".

Other novel exendin agonists are described in PCT Application Serial No. PC'r/US98/24278, entitled "Novel Exendin Agonist Compounds".

SUMMARY OF THE INVENTION According to one aspect, the present invention provides novel exendin agonist compounds which exhibit advantageous properties which include effects in slowing gastric emptying and lowering plasma glucose levels.

According to the present invention, provided are compounds of the formula [SEQ. ID. NO. 4]: Xaa, Xaa, Xaa 3 Xaa, Xaa% ,Xaa, Xaa, Xaa 6 Xaa 9 Xaa 10 Xaa 11 Xaa 1 2 Xaa 13 Xaa 1 4 Xaa,, Xaa,, Xaa,, Ala Xaaj, Xaa 2 0 Xaa 21 Xaa,..Xaa,, Xaa, 4 Xaa, 5 Xaa 2 Xaa 2 Xaa, 8 -ZI; wherein Xaa, is His, Arg, Tyr, Ala, Norval, Val or Norleu; Xaa, is Ser, Gly, Ala or Thr; Xaa 3 is Ala, Asp or Glu; Xaa, is Ala, Norval, Val, Norleu or Gly; Xaa, is Ala or Thr; Xaa, is Phe, Tyr or naphthylalanine; Xaa, is Thr or Ser; Xaa, is Ala, Ser or Thr; Xaa 9 is Ala, Norval, Val, Norleu, Asp or Glu; Xaa 10 is Ala, Leu, Ile, Val, pentylglycine or Met; Xaa 21 is Ala or Ser; Xaa 12 is Ala or Lys; Xaa 1 3 is Ala or Gln; Xaa 14 is Ala, Leu, Ile, pentyliycine, Val or Met; Xaa 1 is Ala or Glu; Xaa,, is Ala or Glu; Xaa 1 is Ala or Glu; Xaa, 9 is Ala or Val; Xaa 20 is Ala or Arg; /0 Xaa, is Ala or Leu; Xaa., is Phe, Tyr or naphthylalanine; Xaa 23 is Ile, Val, Leu, pentyiglycine, tert-butyiglycine or Met; Xaa 2 4 is Ala, Glu or Asp; Xaa 2 l is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa, 6 is Ala or Leu; Xaa,., is Ala or Lys; Xaa 2 8 is Ala or Asn; Z, is -OH,

-NH,,

Gly-Z 2 Gly G ly-Z,, Gly Gly Xaa 3

Z

2 Gly Gly Xaa 3 1 Ser-Z., Gly Gly Xaa 3 1 Ser Ser-Z 2 Gly Gly Xaa 31 Ser Ser Gly-Z., Gly Gly Xaa 3 1 Ser Ser Gly Ala-Z,, Gly Gly Xaa 31 Ser Ser Gly Ala Xaa, 6 Gly Gly Xaa 3 1 Ser Ser Gly Ala Xaa,, Xaa 3 7

-Z,

Gly Gly Xaa 3 Ser Ser Gly Ala Xaa 36 Xaa 3 Xaa 3

,-Z

2 or Gly Gly Xaa.

1 Ser Ser Gly Ala Xaa 36 Xaa.

1 Xaa 38 Ser wherein Xaa,,, Xaa, 6 Xaa 37 and Xaa3, are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, S N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; and Z, is -OH or -NH,; provided that no more than three of Xaa., Xaa,, Xaa 5 Xaa., Xaa., Xaa 9 Xaa 1 0 Xaa 1 2 Xaa,,, Xaa, 1 Xaa 3 4 Xaa 1 5 Xaa 1 Xaa 1 Xaa 1 Xaa 20 Xaa 2 1 Xaa 2 4 Xaa 2 Xaa 26 Xaa 2 and Xaa 2 s are Ala; and provided also that, .if Xaa, is His, Arg or Tyr, then at least one of Xaa 3 1 Xaa, and Xaaq is Ala.

Also included within the scope of the present invention are pharmaceutically acceptable salts of the-compounds of formula IS and pharmaceutical compositions including said compounds and salts thereof.

Also within the scope of the present invention are narrower genera of peptide compounds of various lengths, for example, genera of compounds which do not include peptides having a length of 28, 29 or 30 amino acid residues, respectively.

Additionally, the present invention includes narrower genera of peptide compounds having particular amino acid sequences, for example, compounds of formula [SEQ. ID.

NO. 111J Xaa, Xaa. Xaa3 Xaa 4 Xaa 5 Xaa, Xaa 7 Xaa 8 Xaa, Xaa 10 Xaa,, Xaa 3 2 Xaa 1 Xaa 1 4 Xaa,, 5 Xaa 1 6 Xaa,, Ala Xaa 1 9 Xaa 2 0 Xaa 2 Xaa 22 Xaa 23 Xaa 2 Xaa 2 Xaa, Xaa 2 Xaa 2

,-Z

1 wherein Xaaj is His or Ala; Xaa, is Gly or Ala; Xaa, is Ala, Asp or Glu; Xaa, is Ala or Cly; SXaa, is Ala or Thr; Xaa 6 is Phe or naphthylalanine; Xaa, is Thr or Ser; Xaa, is Ala, Ser or Thr; Xaa, is Ala, Asp or Glu; /0Xaa 10 is Ala, Leu or pentyiglycine; Xaa]] is Ala or Ser; Xaa 1 is Ala or Lys; Xaa 13 is Ala or Gin; Xaa,, is Ala, Leu, Met or pentylglycine; IS Xaa,, is Ala or Glu; Xaa 16 is Ala or Glu; Xaa., is Ala or Glu; Xaa 1 is Ala or Val; Xaa, 0 is Ala or Arg; L Xaa 2 1 is Ala or Leu; Xaa 22 i S Phe or naphthylalanine; Xaa.

3 is Ile, Val or tert-butylglycine; Xaa, 4 is Ala, Glu or Asp; Xaa, is Ala, Trp or Phe; Xaa 26 is Ala or Leu; X a is Ala or Lys; Xaa 2 8 is Ala or Asn; Z, is -OH,

-NH

2 Gly-Z., Gly Gly-Z, Gly Gly Xaa,,-Z, Gly Gly Xaa 3 1 Ser-Z, Gly Gly Xaa 3 1 Ser Ser-Z, Gly Gly Xaa 3 1 Ser Ser Gly-Z,, Gly Gly Xaa 31 Ser Ser Gly Ala-Z,, Gly Gly Xaa3 1 Ser Ser Gly Ala Xaa36Z2 Gly Gly Xaa31 Ser Ser Gly Ala Xaa.

6 Xaa 3 /0 Gly Gly Xaa 31 Ser Ser Gly Ala Xaa,, Xaa 3 Xaa 3 Gly Gly Xaa 3 Ser Ser Gly Ala Xaa:j, Xaa 3 Xaa 3 Ser-Z..; Xaa 2 1 Xaa 3 Xaa 3 and Xaa 3 are independently Pro, homoproline, thioproline, or N-methylylalanine; and is -OH or -NH 2 provided that no more than three of Xaa,, Xaa., XaaE., Xaa 8 Xaa 1 0 Xaa H' Xaa, 1 Xaa, 3 Xaa 14 Xaa 1 Xaa 1 Xaal., Xaa 1 Xa., Xaa,, Xaa, 4 Xaa.., Xaa,, and Xaa,~ are Ala; and provided that, if Xaa, is His, Arg or Tyr, then at least one of Xaa,, Xaa, and Xaa 9 is Ala; and pharmaceutically acceptable salts thereof; Also provided are peptide compounds of the formula (II) [SEQ. ID. NO. 94]: Xaa 2 Xaa. Xaa 3 Xaa, Xaa 5 Xaa, Xaa., Xaa, Xaa, Xaa 1 0 '2S Xaa 1 1 Xaa 1 2 Xaa.

3 Xaa, 4 Xaa 1 Xaa 1 Xaa 1 Ala XaaQ Xaa 20 Xaa 2 1 Xaa., Xaa 2 1 Xaa 24 Xaa, Xaa 2 6

X

1

-Z

1 wherein Xaa 1 is His, Arg, Tyr, Ala, Norval, Val, Norleu or 4imidazopropionyl; Xaa. is Ser, Gly, Ala or Thr; Xaa 3 is Ala, Aspor Glu; Xaa, is Ala, Norval, Val, Norleu or Gly; Xaa 5 is Ala or Thr; riXaa, is Phe, Tyr or naphthylalanine; Xaa, is Thr or Ser; IND Xaa, is Ala, Ser or Thr; Xaa, is Ala, Norval, Val, Norleu, Asp or Glu; Xaa, 0 is Ala, Leu, Ile, Val, pentylglycine or Met; IND Xaa,, is Ala or Ser; (0tc Xaa 1 2 is Ala or Lys; Xaa,, is Ala or Gln; Xaa 1 is Ala, Leu, Ile, pentylqlycine, Val or Met; Xaa 1 5 is Ala or Glu; Xaa,, is Ala or Glu; ISXaa, is Ala or Glu; Xaa 19 is Ala or Val; Xaa 20 is Ala or Arg; Xaa.

1 is Ala, Leu or Lys-NH t -R where R is Lys, Arq, C-clO straight chain or branched alkanoyl or cycloalleyl-alkanoyl; Xaa,, is Phe, Tyr or naphthylalanine; Xaa, 3 is Ile, Val, Leu, pentylqlycine, tert-butylglycine or Met; Xaa,, is Ala, Glu or Asp; Xaa,, is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa 2 6 is Ala or Leu; 2$ X, is Lys Asn, Asn Lys, Lys-N-I-R Asn, Asn Lys-NH*-R, Lys-NHc-R Ala, Ala Lys-NH t -R where R is Lys, Arg, straight chain or branched alkanoyl or cycloalkylalkanoyl Z, is -OH,

-NH

2 1 Gly-Z, Gly Gly-Z, Gly Gly Xaa 31

-Z

2 Gly Gly xaa 31 Ser-Z., Gly Xaa 3 Ser Ser-Z, Gly Gly Xaa,, Ser Ser Gly-Z,, Gly Gly Xaa 31 Ser Ser Gly Ala-Z-,, Gly Gly Xaa 3 Ser Ser Gly Ala Xaa 36

-Z

2 Gly Gly Xaa3, Ser Ser Gly Ala Xaa,, Xaa 3 to Gly Gly Xaa., Ser Ser Gly Ala Xaa 36 Xaa 3 or Gly Gly Xaa 31 Ser Ser Gly Ala Xaa 36 Xaa 3 Xaa., Xaa 3 wherein Xaa 3 1 Xaa 3 Xaa 3 and Xaa, 0 are independently selected from the group consisting of Pro, 3H-yp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine; and is -OH or -NH,; provided that no more than three of Xaa,, Xaa,, Xaa,,, Xaa 6 Xaa.

2o ~Xaa 9 Xaaj 0 Xaall, Xaa 1 Xaa, 1 Xaal,., Xaa,, Xaa,, Xaa Xaa), Xaa 20 Xaa, 1 Xaa 2 1, Xaa.., Xaa 2 1, are Ala; and provided also that, if Xaa, is His, Arg, Tyr, or 4 -imidazopropionyl then at least one of Xaa 3 Xaa, and Xaa 9 is Ala.

Also within the scope of the present invention are SS pharmaceutically acceptable salts of the compounds of formula (II) and pharmaceutical compositions including said compounds and salts thereof.

Preferred compounds of formula (II) include those wherein Xaa, is His, Ala, Norval or 4 -imidazopropionyl. Preferably,

ID

(N

cO'-S 12 Xaa, is His, or 4-imidazopropionyl or Ala, more preferably His or 4-imidazopropionyl.

Preferred compounds of formula (II) include those wherein Xaa, is Gly.

Preferred compounds of formula (II) include those wherein Xaa, is Ala.

Preferred compounds of formula (II) include those wherein Xaa 1 is Leu, pentylglycine or Met.

Preferred compounds of formula (II) include those wherein Xaa, 5 is Trp or Phe.

Preferred compounds of formula (II) include those wherein Xaa 6 is Ala, Phe or naphthylalanine; Xaa,, is Phe or naphthylalanine; and Xaa, 3 is Ile or Val.

Preferred compounds of formula (II) include those wherein Z, is -NH,.

Preferred compounds of formula (II) include those wherein Xaa 3 Xaa 36 Xaap and Xaa,, are independently selected from the group consisting of Pro, homoproline, thioproline and Nalkylalanine.

Preferred compounds of formula (II) include those wherein Xaa 39 is Ser or Tyr, preferably Ser.

Preferred compounds of formula (II) include those wherein Z is -NH,.

Preferred compounds of formula (II) include those 42 wherein Z, is -NH,.

2s Preferred compounds of formula (II) include those wherein Xaa 2 1 is Lys-NH-R where R is Lys, Arg, C,-C, 0 straight chain or branched alkanoyl.

Preferred compounds of formula (II) include those wherein X, is Lys Asn, Lys-NH'-R Asn, or Lys-NH'-R Ala where R is Lys, Arg, straight chain or branched alkanoyl.

Preferred compounds of formula (II) include those having an amino acid sequence selected from SEQ. ID. NOS. 95-110.

Definitions In accordance with the present invention and as used herein, the following terms are defined to have the following meanings, unless explicitly stated otherwise.

(0 The term "amino acid" refers to natural amino acids, unnatural amino acids, and amino acid analogs, all in their D and L stereoisomers if their structure allow such stereoisomeric forms. Natural amino acids include alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), IS gluramine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), Lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), typtophan (Trp), tyrosine (Tyr) and valine (Val). Unnatural amino acids include, but are not limited to 2C azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2 -aminoisobutyric acid, 3 -aminoisbutyric acid, 2-aminopimelic acid, tertiary-butylglycine, 2, 4 -diaminoisobutyric acid, desmosine, 2 2 '-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3 -hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid and thioproline. Amino acid analogs include the natural and unnatural amino acids which are chemically blocked, reversibly or irreversibly, or modified on their N-terminal amino group or their side-chain groups, as for example, methionine sulfoxide, methionine sulfone, S-(carboxymethyl)cysteine, S-(carboxymethyl)-cysteine sulfoxide and S- (carboxymethyl)-cysteine sulfone.

The term "amino acid analog" refers to an amino acid wherein either the C-terminal carboxy group, the N-terminal amino group or side-chain functional group has been chemically codified to another functional group. For example, aspartic acid-(beta-methyl ester) is an amino acid analog of aspartic acid; N-ethylglycine is an amino acid analog of glycine; or alanine carboxamide is an amino acid analog of alanine.

The term "amino acid residue" refers to radicals having the structure: wherein R typically is wherein R' is an amino acid side chain, typically H or a carbon containing substitutent; or (2)

H

2 wherein p is 1, 2 or 3 representing the azetidinecarboxylic acid, proline or pipecolic acid residues, respectively.

The term "lower" referred to herein in connection with organic radicals such as alkyl groups defines such groups with up to and including about 6, preferably up to and including 4 and advantageously one or two carbon atoms. Such groups may be straight chain or branched chain.

"Pharmaceutically acceptable salt" includes salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid. In practice the use of the salt form amounts to use of the base form. The compounds of the present invention are useful in both free base and salt form, with both forms being considered as being within the scope of the present invention.

In addition, the following abbreviations stand for the following: "ACN" or "CH 3 CN" refers to acetonitrile.

"Boc", "tBoc" or "Tboc" refers to t-butoxy carbonyl.

"DCC" refers to N,N'-dicyclohexyicarbodiimiae.

"Fmoc" refers to fluorenylmethoxycarbonyl.

"HBTU" refers to 2 -(1H-benzotriazoi-!-yl)- 1,1,3, 3 ,-tetramethyluronium hexaflurophcsphate.

"HOBt" refers to l-hydroxybenzotriazole monohycrate.

"homoP" or hPro" refers to homoproline.

"MeAla" or "Nme" refers to N-methylalanine.

"naph" refers to naphthylalanine.

"pG" or pGly" refers to pentylglycine.

"tBuG" refers to tertiary-butylglycine.

2 "ThioP" or tPro" refers to thioproline.

3 Hyp" refers to 3 -hydroxyproline "4Hyp" refers to 4 -hydroxyproline "NAG" refers to N-alkylglycine "NAPG" refers to N-alkylpentylglycine EN ""Norval" refers to norvaline "Norleu" refers to norleucine C BRIEF DESCRIPTION OF THE DRAWINGS IN Figure 1 depicts the amino acid sequence for exendin-3 S S [SEQ. ID. NO. 1].

CA Figure 2 depicts the amino acid sequence for exendin-4 \O [SEQ. ID. NO. 2].

Q Figure 3 depicts the amino acid sequence for GLP-1[7-36]NH 2 (GLP-1) [SEQ. ID. NO. 3].

to Figure 4 depicts the amino acid sequences for certain compounds of the present invention, Compounds 1-89 [SEQ. ID.

NOS. 5 to 93].

Figure 5 depicts the effect on lowering blood glucose of various concentrations of Compound 1 [SEQ. ID. NO. s Figure 6 depicts a comparison of effects on gastric emptying of various concentrations of Compound 1 [SEQ. ID. NO.

Figure 7 depicts the amino acid sequences for certain compounds of the present invention, Compound Nos. 90-105 [SEQ.

2O ID. NOS. 95-110].

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, provided are compounds of the formula [SEQ. ID. NO. 4]: Xaa, Xaa, Xa a 2 Xaa 4 Xaa, Xaa( Xaa., xaa, Xaa,, Xaa 10 Xaa 11 Xaa,, Xaa,, Xaa 1 4 Xaaf, Xaa,, Ala Xaa 1 Xaa,,% Xaa 2 l Xaa-~ Xaa.,~ Xaa 24 Xaa,~ Xaa., Xaa 27 wherein Xaa 1 is His, Arg, Tyr, Ala, Norval, Val or Norleu; Xaa, is Ser, Gly, Ala or Thr; Xaa, is Ala, Asp or Glu; Xaa 4 is Ala, Norval, Val, Norleu or Gly; Xaab is Ala or Thr; Xaa, is Phe, Tyr or naphthylalanine; Xaa, is Thr or Ser; Xaa, iJs Ala, Ser or Thr; Xaa 9 is Ala, Norval, Val, Norleu, Asp or Glu; Xaa,, is Ala, Leu, Ile, Val, pentylglycine or Met; IS Xaa,, is Ala or Ser; Xaa,. is Ala or Lys; Xaa, 3 is Ala or Gin; Xaa 1 4 is Ala, Leu, Ile, pentyiglycine, Val or Met; Xaa 15 is Ala or Glu; Xaa,, is Ala or Glu; Xaa 1 is Ala or Glu; Xaa~ 9 i s Ala or Val; Xaa, 0 is Ala or Arg; Xaa., is Ala, Leu or Lys-NHLR where R is Lys, Arg, C,-CiO straight chain or branched alkanoyl or cycloalleyl-alkanoyl; Xaa-, is Phe, Tyr or naphthylalanine; Xaa.

3 is Ile, Val, Leu, pentylglycine, tert-butyiglycine or Met; Xaa, is Ala, Giu or Asp; Xaa 2 is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa,, is Ala or Leu; Xaa,, is Ala or Lys; Xaa 2 8 is Ala or Asn; Z, is -OH,

-NH

2 Gly-Z.,, Gly Gly-Z,, Gly Gly Xaa,,Z2 Gly Gly Xaa 31 Ser-Z 2 Gly Gly Xaa 3 1 Ser Ser-Z.,, Gly Gly Xaa 3 1 Ser Ser Gly-Z, Gly Gly Xaa3 1 Ser Ser Gly Ala-Z,, Gly Gly Xaa 3 1 Ser Ser Gly Ala Xaalr-,, Gly Gly Xaa 3 1 Ser Ser Gly Ala Xaa 3 Xaa-,.Z,, Gly Gly Xaa,, Ser Ser Gly Ala Xaa 3 Xaa,, or Gly Gly Xaa 31 Ser Ser Gly Ala Xaa 3 Xaa,- Xaa 1 Xaa,,-Z,; wherein Xaa~l, Xaa 36 Xaa 3 and Xaa,, are independently: selected from Pro, homoprol-ine, 3Hiyp, 4Hyp, 'r~ioproline,

N-

alkyiglycine, N-alkylpentylglycine or N-alkylalanine; and

Z

2 is -OH or -NH,; provided that no more than three of Xaa,, Xaa,, Xaa,, Xaa 6 Xaa, Xaa 9 Xaa 10 Xaal 1 Xaa 12 I Xaa 1 3 Xaa 1 4 Xaa,,, Xaal(., X aa 1 Xaa 19 Xaa 20 Xaa, 1 Xaa 2 4 Xaa 2 Xaa 2 6 Xaa 2 .7 and Xaa,, are Ala; and provided also that, if Xaa, is His, Arg or Tyr, then at least one of Xaa 3 Xaa, and Xaa, is Ala. Also within the scope of the present invention are pharmaceutically acceptable salts of formula and pharmaceutic compositions including said compounds and salts thereof.

Preferred N-alkyl groups for N-alkylglycine,

N-

alkylpentylglycine and N-alkylalanine include lower alkyl groups preferably of 1 to about 6 carbon atoms, more preferably of 1 to 4 carbon atoms. Suitable compounds of formula include those identified in Examples 1-89 ("Compounds 1-89," respectively) [SEQ. ID. NOS. 5 to 93], as well as those corresponding compounds identified in Examples 104 and 105.

Preferred such exendin agonist compounds include those wherein Xaa, is His, Ala or Norval. More preferably Xaa, is His 0 O or Ala. Most preferably Xaa, is His.

Preferred are those compounds of formula wherein Xaa, is Gly.

Preferred are those compounds of formula wherein Xaa, is Ala.

Preferred are those compounds of formula wherein Xaa 4 is Ala.

Preferred are those compounds of formula wherein Xaa, is Ala.

Preferred are those compounds of formula wherein Xaa,, is Leu, pentylglycine or Met.

Preferred compounds of formula are those wherein Xaa, 2 is Trp or Phe.

Preferred compounds of formula are those where Xaa, is Ala, Phe or naphthylalanine; Xaa 2 2 is Phe or naphthylalanine; and Xaa, 2 is Ile or Val.

Preferred are compounds of formula wherein Xaa 3 Xaa 3 Xaa., and Xaa,, are independently selected from Pro, homoproline, thioproline and N-alkylalanine.

Preferably Zi is -NH,.

Preferably Z, is -NH,.

According to one aspect, preferred are compounds of formula wherein Xaa, is Ala, His or Tyr, more preferably Ala or His; Xaa 2 is Ala or Gly; Xaa 6 is Phe or naphthylalanine; Xaa,, is Ala, S Leu, pentylglycine or Met; Xaa 2 2 is Phe or naphthylalanine; Xaa 2 3 is Ile or Val; Xaa 3 l, Xaa 3 Xaa,, and Xaa,, are independently selected from Pro, homoproline, thioproline or N-alkylalanine; and Xaa~ 9 is Ser or Tyr, more preferably Ser. More preferably

Z

1 i s -Nil 2 /0 According to an especially preferred aspect, especially preferred compounds include those of formula wherein: Xaa 1 is His or Ala; Xaa, is Gly or Ala; Xaa 3 is Ala, Asp or Glu; Xaa 4 is Ala or Gly; Xaa, is Ala or Thr; Xaa, is Phe or naphthylalanine; Xaa, is Thr or Ser; Xaa, is Ala, Ser or Thr; Xaa, is Ala, Asp or Glu; Xaa1 0 is Ala, Leu or pentylglycine; Xaa 11 is Ala or Ser; Xaa 12 is Ala or Lys; Xaa,, is Ala or Gln; Xaa1 4 is Ala, Leu, Met or pentylglycine; Xaa 5 is Ala or Glu; Xaal, is Ala or Glu; Xaa, is Ala or Glu; Xaa 1 9 is Ala or Val; Xaa,, is Ala or Arg; Xaa 21 is Ala or Leu; Xaa 22 is Phe or naphthylalanine; Xaa 2 3 0 is Ile, Val or tert-butyiglycine; Xaa 24 is Ala, Glu or Asp; Xaa 2 is Ala, Trp or Phe; Xaa 2 6 is Ala or Leu; Xaa 2 is Ala or Lys; Xaa,, is Ala or Asn; Z, is -OH, -NH 2 Gly-Z,, Gly Gly-Z,, Gly Gly Xaa 31

-Z

2 Gly Gly Xaa,, Ser-Z 2 Gly Gly Xaa 3 1 Ser Ser-Z,, Gly Gly Xaa 3 l Ser Ser Gly-Z,, Gly Gly Xaa~l Ser Ser Gly Ala-Z 2 Gly Gly S Xaa 3 1 Ser Ser Gly Ala Xaa3,-Z 2 Gly Gly Xaa,, Ser Ser Gly Ala Xaa 36 Gly Gly Xaa 3 1 Ser Ser Gly Ala Xaa 36 Xaa 3 Xaa 3

,-Z

2 or Gly Gly Xaa,, Ser Ser Gly Ala Xaa 3 6 Xaa 3 Xaa 3 Xaa 3 9

-Z

2 Xaa 3 Xaa 3 Xaa., and Xaa 3 being independently Pro homoproline, thioproline or N-methylalanine; and Z, being -OH or -NH 2 provided that no more than three of Xaa 3 Xaa,, Xaa 6 Xaa, Xa a 1 0 Xaa,,, Xaa 1 Xaa Xaa14, Xaals, Xaal., Xaa 1 Xaa,,, Xaa20 Xaa 21 Xaa24, Xaa2s Xaa 26 Xaa 2 and Xaa 28 are Ala; and provided also that, if Xaa, is His, Arg or Tyr, then at least one of Xaa,, Xaa 4 and Xaa, is Ala.

Especially preferred compounds of formula include those having the amino acid sequence of SEQ. ID. NOS. 5-93 According to an especially preferred aspect, provided are compounds of formula where Xaa 24 is Ala, Leu, Ile, Val or pentylglycine, more preferably Leu or pentylglycine, and Xaa 2 is Ala, Phe, Tyr or naphthylalanine, more preferably Phe or naphthylalanine. These compounds will be less susceptible to oxidative degration, both in vitro and in vivo, as well as during synthesis of the compound.

Additionally, the present invention includes narrower genera of peptide compounds having particular amino acid sequences, for example, compounds of the formula [SEQ. ID.

0 NO. 4]: Xaa, Xaa, Xaa 3 Xaa, Xaa, Xaa, Xaa, Xaa 8 Xaa, XaaloXaa,, Xaa,2 Xaa 1 3 Xaa,, Xaa, 5 Xaa,, Xaa,, Ala Xaa, 8 Xaa,, Xaao Xaa,, Xaa. Xaa, 3 Xaa,, Xaa,, Xaa 26 Xaa 2 wherein Xaa, is His or Ala; 21 Xaa, is Gly or Ala; Xaa 3 is Ala, Asp or Glu; Xaa 4 is Ala or Gly;

IND

Xaa, is Ala or Thr; Xaa 6 i S Phe or naphthylalanine; Xaa, is Thr or Ser; Xaa, is Ala, Ser or Thr; Xaa, is Ala, Asp or Glu; Xaa 10 is Ala, Leu or pentylqlycine; Xaa 11 is Ala or Ser; Xaa 12 is Ala or Lys; Xaa 13 is Ala or Gin; Xaal, is Ala, Leu, Met or pentylglycine; Xaa 15 is Ala or Glu; Xaa 16 is Ala or Glu; Xaa 1 7 is Ala or Glu; Xaa 19 is Ala or Val; Xaa~c, is Ala or Arg; Xaa, 1 is Ala or Leu; Xaa,. is Phe or naphthylalanine; Xaa, 3 is Ile, Val or tert-butyiglycine; Xaa 24 is Ala, Glu or Asp; Xaa, is Ala, Trp or Phe; Xaa, 6 is Ala or Leu; Xaa., is Ala or Lys; Xaa 2 l, is Ala or Asn; Z, is -OH, -N H 2 Gly-Z 2 Gly Gly-Z 2 Gly Gly Xaa 3

Z

2 Gly Gly Xaa3 1 Ser-Z 2 1 Gly Gly Xaa 3 1 Ser Ser-Z,, Gly Gly Xaa 3 1 Ser Ser Gly-Z,, Gly Gly Xaa~l Ser Ser Gly Ala-Z.., Gly Gly Xaa 3 Ser Ser Gly Ala Gly Gly Xaa 3 1 Ser Ser Gly Ala Xaa 36 Xaa 3 Gly Gly Xaa 31 Ser Ser Gly Ala Xaa, 6 Xaa 3 Xaa 3 Gly Gly Xaa 31 Ser Ser Gly Ala Xaa 3 6 Xaa3- Xaa 3 Ser-Z.; Xaa 31 Xaa 3 6 Xaa 3 and Xaa 3 are independently Pro, homoproline, thioproline, or N-methylylalanine; and Z, is -OH or-N, provided that no more than three of Xaa 3 Xaa,, Xaa., Xaa, Xaa 10 Xaa 11 Xaa:? Xaa, 1 Xaa, 4 Xaa 1 6 Xaa 1 XaaI9, Xaa2 0 Xaa 2 l, Xaa 24' Xaa 2 Xaa 2 6 Xaa 2 and Xaa, are Ala; and provided that, if Xaa 1 is His, Arg or Tyr, then at least one of Xaa 3 Xaa, and Xaa, is Ala; and pharmaceutically acceptable salts thereof; Also provided are peptide compounds of the formula (II) [SEQ. ID. NO. 94]: Xaa, Xaa. Xaa, Xaa 4 Xaa5 Xaa, Xaa, Xaa, Xaa, Xaa 1 XaaI 1 Xaa,, Xaa)3 Xaa 14 Xaa 1 Xaa 16 Xaa 1 Ala Xaa) 9 Xaa.- 0 Xa, a.

Xa a aa 2 Xaa 2 Xaa 2 Xaa 2 6

X-

1 wherein Xaaj is His, Arg, Tyr, Ala, Norval, Val, Norleu or 4imidazopropionyl; Xaa i s Ser, Gly, Ala or Thr; Xaa 3 is Ala, Asp or Glu; Xaa 4 is Ala, Norval, Val, Norleu or Gly; Xaa, is Ala or Thr; Xaa, is Phe, Tyr or naphthylalanine; Xaa, is Thr or Ser; Xaa, i s Ala, Ser or Thr; Xaa. is Ala, Norval, Val, Norleu, Asp or Glu; Xaa 1 O is Ala, Leu, TIe, Val, pentyliycine or Met; SXaa 1 is Ala or Ser; Xaa 1 2 is Ala or Lys; Xaaj, is Ala or Gin; Xaa 14 is Ala, Leu, Ile, pentyiglycine, Val or Met; Xaa 15 is Ala or Giu; Xaa, 6 is Ala or Giu; Xaaj, is Ala or Glu; Xaa 19 is Ala or Val; Xaa 20 is Ala or Arg; Xaa 2 l is Ala, Leu or Lys-NH'-R where R is Lys, Arg, C-clO straight chain or branched aikanoyl or cycloalleyl-aikanoyl; Xaa., is Phe, Tyr or naphthyiaianine; Xaa.

3 is Ile, Val, Leu, pentyiglycine, tert-butyiglycine or Met; Xaa, 4 is Ala, Giu or Asp; Xaa-. is Ala, Trp, Phe, Tyr or naphthyiaianine; Xaa, 6 is Ala or Leu; X, is Lys Asn, Asn Lys, Lys-NH%,R Asn, Asn Lys-NHu-R, Lys-NH'-R Ala, Ala Lys-NHc-R where R is Lys, Arg, C 1 -C1O straight chain or branched aikanoyl or cycloalkylalkanoyl Z, is -OH,

-NH,,

Gly-Z21 Gly Gly-Z 2 1 Gly Gly Xaa3 1 Gly Gly Xaa~l Ser-Z, Gly Gly Xaa 2 1 Sex Ser-Z, Gly Gly Xaa 3 1 Ser Sex Gly-Z 2 Gly Gly Xaa 3 1 Sex Ser Gly Ala-Z, Gly Gly Xaa 3 S er Sex Gly Ala Xaa 3 6 Gly Xaa,, Ser Ser Gly Ala Xaa 36 Xaa 3 7

-Z

2 Gly Gly Xaa 3 Ser Ser Gly Ala Xaa 3 G Xaa 3 Xaa 3 8 or Gly Gly Xaa 3 Ser Ser Gly Ala Xaa Xaa Xaa aa-Z,; wherein IND Xaa3, Xaa 3 6 Xaa 3 and Xaa 38 are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine; and Z, is -OH or -NH.; Is provided that no more than three of Xaa,, Xaa 4 Xaa,, Xaa,, Xaa 8 Xaaq, Xaaj 0 Xaall, Xaa-,, Xaa 13 Xaa,,, Xaa, 5 Xaa 6 Xaa,, Xaa 19 Xaa 2 Xaa,,, Xaa 24 Xaa 2 Xaa.

6 are Ala; and provided also that, if Xaal is His, Arg, Tyr, or 4-imidazopropionyl then at least one of Xaa,, Xaa 4 and XaaQ, is Ala.

Also within the scope of the present invention are pharmaceutically acceptable salts of the compounds of formula (II) and pharmaceutical compositions including said compounds and salts thereof.

Preferred compounds of formula (II) include those wherein D- Xaa, is His, Ala, Norval or 4-imidazopropionyl. Preferably, Xaa, is His, or 4-imidazopropionyl or Ala, more preferably His or 4 -imidazopropionyl.

Preferred compounds of formula (II) include those wherein Xaa. is Gly.

IO

D 26 Preferred compounds of formula (II) include those wherein 0 Xaa 4 is Ala.

Preferred compounds of formula (II) include those wherein C1 Xaa, is Ala.

Preferred compounds of formula (II) include those wherein IN Xaa 4 is Leu, pentylglycine or Met.

i Preferred compounds of formula (II) include those wherein

C

Xaa, is Trp or Phe.

IN Preferred compounds of formula (II) include those wherein D /O Xaa 6 is Ala, Phe or naphthylalanine; Xaa,, is Phe or naphthylalanine; and Xaa,, is Ile or Val.

Preferred compounds of formula (II) include those wherein Z is -NH,.

Preferred compounds of formula (II) include those wherein SXaa 3 Xaa 36 Xaa 3 and Xaa,, are independently selected from the group consisting of Pro, homoproline, thioproline and Nalkylalanine.

Preferred compounds of formula (II) include those wherein Xaa39 is Ser or Tyr, preferably Ser.

Preferred compounds of formula (II) include those wherein Z. is -NH,.

Preferred compounds of formula (II) include those 42 wherein Z, is -NH,.

Preferred compounds of formula (II) include those wherein S Xaa,, is Lys-NH'-R where R is Lys, Arg, straight chain or branched alkanoyl.

Preferred compounds of formula (II) include those wherein X, is Lys Asn, Lys-NHc-R Asn, or Lys-NHc-R Ala where R is Lys, Arg, C,-C 0 straight chain or branched alkanoyl.

SPreferred compounds of formula (II) include those having an Samino acid sequence selected from SEQ. ID. NOS. 95-110.

SThe compounds referenced above form salts with various inorganic and organic acids and bases. Such salts include salts prepared with organic and inorganic acids, for example, HC1, HBr, HSO, H 3 PO0, trifluoroacetic acid, acetic acid, formic V acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, (N fumaric acid and camphorsulfonic acid. Salts prepared with Sbases include ammonium salts, alkali metal salts, e.g. sodium SO and potassium salts, and alkali earth salts, e.g. calcium and magnesium salts. Acetate, hydrochloride, and trifluoroacetate salts are preferred. The salts may be formed by conventional means, as by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.

Utility d The compounds described above are useful in view of their pharmacological properties. In particular, the compounds of the invention are exendin agonists, and possess activity as agents to regulate gastric motility and to slow gastric emptying, as evidenced by the ability to reduce post-prandial glucose levels z2 in mammals.

The compounds of the present invention are useful in in vitro and in vivo scientific methods for investigation of exendins and exendin agonists for example in methods such as those described in Examples A-E below.

Preparation of Compounds The compounds of the present invention may be prepared using standard solid-phase peptide synthesis techniques and preferably an automated or semiautomated peptide synthesizer.

S Typically, using such techniques, an a-N-carbamoyl protected amino acid and an amino acid attached to the growing peptide chain on a resin are coupled at room temperature in an inert solvent such as dimethylformamide, N-methylpyrrolidinone or methylene chloride in the presence of coupling agents such as O dicyclohexylcarbodiimide and l-hydroxybenzotriazole in the presence of a base such as diisopropylethylamine. The a-Ncarbamoyl protecting group is removed from the resulting peptide-resin using a reagent such as trifluoroacetic acid or piperidine, and the coupling reaction repeated with the next desired N-protected amino acid to be added to the peptide chain.

Suitable N-protecting groups are well known in the art, with tbutyloxycarbonyl (tBoc) and fluorenylmethoxycarbonyl (Fmoc) being preferred herein.

The solvents, amino acid derivatives and 4 -methylbenzhydryl-amine resin used in the peptide synthesizer may be purchased from Applied Biosystems Inc. (Foster City, CA) The following side-chain protected amino acids may be purchased from Applied Biosystems, Inc.: Boc-Arg(Mts), Fmoc-Arg(Pmc), Boc-Thr(Bzl), Fmoc-Thr(t-Bu), Boc-Ser(Bzl), Fmoc-Ser(t-Bu), Boc-Tyr(BrZ), Fmoc-Tyr(t-Bu), Boc-Lys(Cl-Z), Fmoc-Lys(Boc), Boc-Glu(Bzl), Fmoc-Glu(t-Bu), Fmoc-His(Trt), Fmoc-Asn(Trt), and Fmoc-Gln(Trt). Boc-His(BOM) may be purchased from Applied Biosystems, Inc. or Bachem Inc. (Torrance, CA). Anisole, dimethylsulfide, phenol, ethanedithiol, and thioanisole may be obtained from Aldrich Chemical Company (Milwaukee, WI).

Air Products and Chemicals (Allentown, PA) supplies HF.

0 Ethyl ether, acetic acid and methanol may be purchased from Fisher Scientific (Pittsburgh, PA).

Solid phase peptide synthesis may be carried out with an automatic peptide synthesizer (Model 430A, Applied Biosystems l^ Inc., Foster City, CA) using the NMP/HOBt (Option 1) system and Cg tBoc or Fmoc chemistry (see, Applied Biosystems User's Manual for the ABI 430A Peptide Synthesizer, Version 1.3B July 1, 1988, 0 (0 section 6, pp. 49-70, Applied Biosystems, Inc., Foster City, CA) with capping. Boc-peptide-resins may be cleaved with HF (-5 0

C

to 0°C, 1 hour). The peptide may be extracted from the resin with alternating water and acetic acid, and the filtrates lyophilized. The Fmoc-peptide resins may be cleaved according l S to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc., 1990, pp. 6-12). Peptides may be also be assembled using an Advanced Chem Tech Synthesizer (Model MPS 350, Louisville, Kentucky).

Peptides may be purified by RP-HPLC (preparative and 0 analytical) using a Waters Delta Prep 3000 system. A C4, C8 or C18 preparative column (10 p, 2.2 x 25 cm; Vydac, Hesperia, CA) may be used to isolate peptides, and purity may be determined using a C4, C8 or C18 analytical column (5 A, 0.46 x 25 cm; Vydac). Solvents TFA/water and B=0.1% TFA/CHCN) may be a delivered to the analytical column at a flowrate of 1.0 ml/min and to the preparative column at 15 ml/min. Amino acid analyses may be performed on the Waters Pico Tag system and processed using the Maxima program. Peptides may be hydrolyzed by vaporphase acid hydrolysis (115 0 C, 20-24 Hydrolysates may be 4 derivatized and analyzed by standard methods (Cohen, et al., The Pico Tag Method: A Manual of Advanced Techniques for Amino Acid Analysis, pp. 11-52, Millipore Corporation, Milford,

MA

(1989)). Fast atom bombardment analysis may be carried out by M-Scan, Incorporated (West Chester, PA). Mass calibration may be performed using cesium iodide or cesium iodide/glycerol.

Plasma desorption ionization analysis using time of flight detection may be carried out on an Applied Biosystems Bio-Ion Smass spectrometer. Electrospray mass spectroscopy may be carried and on a VG-Trio machine.

Peptide compounds useful in the invention may also be prepared using recombinant DNA techniques, using methods now known in the art. See, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d Ed., Cold Spring Harbor (1989).

IS Non-peptide compounds useful in the present invention may be prepared by art-known methods.

Formulation and Administration Compounds of the invention are useful in view of their exendin-like effects, and may conveniently be provided in the tO form of formulations suitable for parenteral (including intravenous, intramuscular and subcutaneous) or nasal, buccal or oral administration. In some cases, it will be convenient to provide an exendin agonist and another anti-gastric-emptying agent, such as glucagon, an amylin, or an amylin agonist, in a single composition or solution for administration together. In other cases, it may be more advantageous to administer another anti-emptying agent separately from said exendin agonist. In yet other cases, it may be beneficial to provide an exendin agonist either co-formulated or separately with other glucose lowering agents -such as insulin. A suitable administration format may best be determined by a medical practitioner for each patient individually. Suitable pharmaceutically acceptable carriers and their formulation are described in standard S formulation treatises, Remington's Pharmaceutical Sciences by E.W. Martin. See also Wang, Y.J. and Hanson, M.A.

"Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers," Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S (1988).

1O Compounds useful in the invention can be provided as parenteral compositions for injection or infusion. They can, for example, be suspended in an inert oil, suitably a vegetable oil such as sesame, peanut, olive oil, or other acceptable carrier. Preferably, they are suspended in an aqueous carrier, ;for example, in an isotonic buffer solution at a pH of about 5.6 to 7.4. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, i0 such as pH buffering agents. Useful buffers include for example, sodium acetate/acetic acid buffers. A form of repository or "depot" slow release preparation may be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following transdermal injection or other form of delivery.

The desired isotonicity may be accomplished using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol, polyols (such as mannitol and sorbitol), or other inorganic or organic solutes. Sodium chloride is preferred particularly for buffers Scontaining sodium ions.

0 The claimed compounds can also be formulated as pharmaceutically acceptable salts acid addition salts) and/or complexes thereof. Pharmaceutically acceptable salts are IN non-toxic salts at the concentration at which they are if administered. The preparation of such salts can facilitate the ,g pharmacological use by altering the physical-chemical IO characteristics of the composition without preventing the S| Ocomposition from exerting its physiological effect. Examples of useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate the administration of higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.

o0 Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. Such salts may be prepared by, for example, reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.

Carriers or excipients can also be used to facilitate administration of the compound. Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. The compositions or pharmaceutical composition can be administered (0 by different routes including intravenously, intraperitoneal, subcutaneous, and intramuscular, orally, topically, or transmucosally.

If desired, solutions of the above compositions may be thickened with a thickening agent such as methyl cellulose.

They may be prepared in emulsified form, either water in oil or oil in water. Any of a wide variety of pharmaceutically acceptable emulsifying agents may be employed including, for example, acacia powder, a non-ionic surfactant (such as a Tween), or an ionic surfactant (such as alkali polyether alcohol sulfates or sulfonates, a Triton).

Compositions useful in the invention are prepared by mixing the ingredients following generally accepted procedures. For example, the selected components may be simply mixed in a blender or other standard device to produce a concentrated 2 mixture which may then be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a buffer to control pH or an additional solute to control tonicity.

For use by the physician, the compounds will be provided in dosage unit form containing an amount of an exendin agonist, with or without -another anti-emptying agent. Therapeutically effective amounts of an exendin agonist for use in the control of gastric emptying and in conditions in which gastric emptying is beneficially slowed or regulated are those that decrease post-prandial blood glucose levels, preferably to no more than about 8 or 9 mM or such that blood glucose levels are reduced as desired. In diabetic or glucose intolerant individuals, plasma glucose levels are higher than in normal individuals. In such individuals, beneficial reduction or "smoothing" of post- I0 prandial blood glucose levels, may be obtained. As will be recognized by those in the field, an effective amount of therapeutic agent will vary with many factors including the patient's physical condition, the blood sugar level or level of inhibition of gastric emptying to be obtained, and other (S factors.

Such pharmaceutical compositions are useful in causing gastric hypomotility in a subject and may be used as well in other disorders where gastric motility is beneficially reduced.

The effective daily anti-emptying dose of the compounds LCO will typically be in the range of 0.001 or 0.005 to about mg/day, preferably about 0.01 or 0.05 to 2 mg/day and more preferably about 0.05 or 0.1 to 1 mg/day, for a 70 kg patient.

The exact dose to be administered is determined by the attending clinician and is dependent upon where the particular compound lies within the above quoted range, as well as upon the age, weight and condition of the individual. Administration should begin at the first sign of symptoms or shortly after diagnosis of diabetes mellitus. Administration may be by injection, preferably subcutaneous or intramuscular. Administration may also be by other routes, for example, by oral, buccal or nasal routes, however .dosages should be increased about 5-10 fold, over injection doses.

Generally, in treating or preventing elevated, inappropriate, or undesired post-prandial blood glucose levels, the compounds of this invention may be administered to patients in need of such treatment in a dosage ranges similar to those given above, however, the compounds are administered more frequently, for example, one, two, or three times a day.

The optimal formulation and mode of administration of compounds of the present application to a patient depend on factors known in the art such as the particular disease or disorder, the desired effect, and the type of patient. While the compounds will typically be used to treat human patients, they may also be used to treat similar or identical diseases in other vertebrates such as other primates, farm animals such as swine, cattle and poultry, and sports animals and pets such as horses, dogs and cats.

To assist in understanding the present invention the following Examples are included which describe the results of a series of experiments. The experiments relating to this invention should not, of course, be construed as specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the invention as described herein and hereinafter claimed.

EXAMPLE 1 Preparation of Compound 1 Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. The above amidated peptide was assembled on dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.). In general, singlecoupling cycles were used throughout the synthesis and Fast Moc (HBTU activation) chemistry was employed. Deprotection (Fmoc group removal)of the growing peptide chain was achieved using piperidine. Final deprotection of the completed peptide resin was achieved using a mixture of triethylsilane (0.2 mL), I( ethanedithiol (0.2 mL), anisole (0.2 mL), water (0.2 mL) and trifluoroacetic acid (15 mL) according to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc.) The peptide was precipitated in ether/water (50 mL) and centrifuged. The precipitate was reconstituted in glacial acetic acid and lyophilized. The lyophilized peptide was dissolved in water). Crude purity was about Used in purification steps and analysis were Solvent A TFA in water) and Solvent B TFA in ACN).

The solution containing peptide was applied to a preparative C-18 column and purified (10% to 40% Solvent B in Solvent A over 40 minutes). Purity of fractions was determined isocratically using a C-18 analytical column. Pure fractions were pooled furnishing the above-identified peptide. Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide gave product peptide having an observed retention time of 19.2 minutes. Electrospray Mass Spectrometry calculated 3171.6; found 3172.

EXAMPLE 2 Preparation of Compound 2 His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, (SEQ. ID.

I0 NO. 6] The above amidated peptide was assembled on dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, Sdeprotected and purified in a similar way to Compound 1. Used in analysis were Solvent A TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide gave product peptide having an observed retention time of 14.9 zo minutes. Electrospray Mass Spectrometry calculated 3179.6; found 3180.

EXAMPLE 3 -4 Preparation of Compound 3 His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID. NO.

7] The above amidated peptide was assembled on dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis were Solvent A TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 37% to 47% Solvent

B

in Solvent A over 30 minutes) of the lyophilized peptide gave product peptide having an observed retention time of 12.2 1$ minutes. Electrospray Mass Spectrometry calculated 3251.6; found 3253.3.

EXAMPLE 4 Preparation of Compound 4 His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID. NO.

8] The above amidated peptide was assembled on dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis were Solvent A TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide gave product peptide having an observed retention time of 16.3 minutes. Electrospray Mass Spectrometry calculated 3193.6; found 3197.

/O EXAMPLE Preparation of Compound Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH [SEQ. ID. NO.

9] The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound LO 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry 255 calculated 3228.6.

EXAMPLE 6 Preparation of Compound 6 His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID. NO.

The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3234.7.

EXAMPLE 7 Preparation of Compound 7 His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 11] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and J Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized Speptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3308.7.

(O EXAMPLE 8 Preparation of Compound 8 His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 12] S The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3250.7 SEXAMPLE 9 Preparation of Compound 9 His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH [SEQ. ID.

I 5 NO. 13] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from (0 the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3252.6.

EXAMPLE Preparation of Compound Ala Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 14] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of M( the product peptide. Electrospray Mass Spectrometry calculated 3200.6.

EXAMPLE 11 Preparation of Compound 11 Ala Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu S Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH [SEQ. ID. NO.

The above-identified amidated peptide is assembled on 4- 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized 2 peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3143.5.

IO

44 EXAMPLE 12 Preparation of Compound 12 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu D Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH [SEQ. ID.

NO. 16]

(N

IN The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from JO the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of IS the product peptide. Electrospray Mass Spectrometry calculated 3214.6.

EXAMPLE 13 Preparation of Compound 13 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu 0 Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NHA [SEQ. ID.

NO. 17] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3157.5.

1R EXAMPLE 14 Preparation of Compound 14 Ala Gly Asp Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 18] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound I 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3184.6.

EXAMPLE Preparation of Compound Ala Gly Asp Gly Ala Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, (SEQ. ID.

NO. 19] SThe above-identified amidated peptide is assembled on 4- 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3127.5.

EXAMPLE 16 Preparation of Compound 16 Ala Gly Asp Gly Thr NaphthylAla Thr Ser Asp Leu Ser Lys Gin Met 2<Z Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH [SEQ.

ID. NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from Sthe resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and S- Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of q the product peptide. Electrospray Mass Spectrometry )calculated 3266.4.

CO EXAMPLE 17 Preparation of Compound 17 Ala Gly Asp Gly Thr Naphthylala Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH,[SEQ.

ID. NO. 21] 1S The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3209.4.

48 EXAMPLE 18 Preparation of Compound 18 Ala Gly Asp Gly Thr Phe Ser Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH 2 [SEQ. ID.

NO. 22] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from 1O the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of IS the product peptide. Electrospray Mass Spectrometry calculated 3200.6.

EXAMPLE 19 Preparation of Compound 19 Ala Gly Asp Gly Thr Phe Ser Ser Asp Leu Ser Lys Gin Leu Glu Glu O Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. 23] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3143.5.

Io EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ala Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 24] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1 Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry 52 calculated 3198.6.

SEXAMPLE 21 Preparation of Compound 21 Ala Gly Asp Gly Thr Phe Thr Ala Asp Leu Ser Lys Gin Leu Glu Glu )Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. )The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of S the product peptide. Electrospray Mass Spectrometry calculated 3141.5.

EXAMPLE 22 Preparation of Compound 22 Ala Gly Asp Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 26] The above-identified peptide is assembled on dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine 'MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B (0.1% .S TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B i in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product 1 peptide. Electrospray Mass Spectrometry calculated 3170.6.

EXAMPLE 23 Preparation of Compound 23 0 Ala Gly Asp Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH [SEQ. ID.

NO. 27] The above-identified amidated peptide is assembled on 4-

S(

2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Z/O Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3113.5.

EXAMPLE 24 Preparation of Compound 24 \0

IN

(C)

Ala Gly Asp Gly Thr Phe Thr Ser Glu Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 28] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3228.6.

EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ser Glu Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. 29] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc- O protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound CRl 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of q the product peptide. Electrospray Mass Spectrometry sD calculated 3171.6.

EXAMPLE 26 Preparation of Compound 26 Ala Gly Asp Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH [SEQ. ID.

NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound D 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry ?c calculated 3172.5.

EXAMPLE 27 SPreparation of Compound 27 Ala Gly Asp Gly Thr Phe Thr Ser Asp Ala Ser Lys Gin Leu Gl *Glu O Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH. [SEQ. ID.

5 NO. 31] The above-identified amidated peptide is assembled on 4-

S(

2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from O the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of S the product peptide. Electrospray Mass Spectrometry calculated 3115.4.

EXAMPLE 28 Preparation of Compound 28 Ala Gly Asp Gly Thr Phe Thr Ser Asp Pentylgly Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID. NO. 32] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and S Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3230.4.

0 EXAMPLE 29 Preparation of Compound 29 Ala Gly Asp Gly Thr Phe Thr Ser Asp Pentylgly Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID. NO. 33] SThe above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3198.6.

EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ala Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

E NO. 34] The above-identified amidated peptide is assembled on 4-

S(

2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from r0 the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of S the product peptide. Electrospray Mass Spectrometry calculated 3141.5.

EXAMPLE 31 Preparation of Comound 31 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ala Lys Gin Leu Glu Glu Zo Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH 2 [SEQ. ID.

NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3157.5.

EXAMPLE 32 Preparation of Compound 32 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH. [SEQ. ID.

NO. 36] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Ao Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3100.4.

Q EXAMPLE 33 SPreparation of Compound 33 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Ala Gin Leu Glu Glu C Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH. [SEQ. ID.

NO. 37] C The above-identified amidated peptide is assembled on 4- D 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3157.6.

EXAMPLE 34 Preparation of Compound 34 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala.Met Glu Glu 12O Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 38] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA .resin (Novabiochem, 0.55 mmole/g) using Fmoc- Sprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound

C

1 i. Used in analysis are Solvent A TFA in water) and S Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry 0 calculated 3100.5.

(o EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala Leu Glu Glu Glu Ala Val Arg Leu Phe lie Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. 39] r The above-identified amidated peptide is assembled on 4- 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry n, calculated 3100.5.

560 EXAMPLE 36 SPreparation of Compound 36 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Ala Glu Glu O Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. S The above-identified amidated peptide is assembled on 4g 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from 0 the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3154.5.

EXAMPLE 37 Preparation of Compound 37 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Ala Glu Glu o Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. 41] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino-acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3115.5.

EXAMPLE 38 Preparation of Compound 38 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Pentylgly Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID. NO. 42] The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3212.4.

EXAMPLE 39 Preparation of Compound 39 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Pentylgly Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID. NO. 43] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from 0 the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3173.4.

EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Ala Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH 2 [SEQ. ID. NO.

44] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc- 63 protected amino-acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to j 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3156.6.

EXAMPLE 41 Preparation of Compound 41 (0 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Ala Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH. [SEQ. ID. NO.

The above-identified amidared peptide is assembled on 4- 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and uC Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3099.5.

EXAMPLE 42 Preparation of Compound 42 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Ala Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn-NH, [SEQ. ID.

4 NO. 46] The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Pmocprotected amino acids (Applied Biosystems, Inc.), cleaved from /0 the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3156.6.

EXAMPLE 43 Preparation of Compound 43 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Ala y Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. 47] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3099.5.

EXAMPLE 44 Preparation of Compound 44 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Ala Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID. NO.

48] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3156.6.

EXAMPLE Preparation of Compound

IN

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Ala Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NHI [SEQ. ID.

NO. 49] The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrome:ry calculated 3099.5.

EXAMPLE 46 Preparation of Compound 46 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID. NO.

The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide e, norleucine MBHA-resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from Sthe resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized m peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3186.6.

EXAMPLE 47 Preparation of Compound 47 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH. [SEQ. ID. NO.

51] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3129.5.

EXAMPLE 48 Preparation of Compound 48 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Ala Leu Phe lie Glu Trp Leu Lys Asn-NH, [SEQ. ID. NO.

52] The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3129.5.

EXAMPLE 49 Preparation of Compound 49 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Ala Leu Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. 53] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3072.4.

'0 EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Ala Phe Ile Glu Trp Leu Lys Asn-NH, [SEQ. ID.

NO. 54] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry Scalculated 3172.5.

EXAMPLE 51 Preparation of Compound 51 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Ala Phe Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID. NO.

The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3115.5.

EXAMPLE 52 Preparation of Compound 52 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Naphthylala Ile Glu Trp Leu Lys Asn-NH 2 [SEQ. ID. NO. 56] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of F0 the product peptide. Electrospray Mass Spectrometry calculated 3266.4.

EXAMPLE 53 Preparation of Compound 53 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Naphthylala Ile Glu Phe Leu Lys Asn-NH, [SEQ. ID. NO. 57] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product pept-ide. Electrospray Mass Spectrometry Scalculated 3209.4.

EXAMPLE 54 Preparation of Compound 54 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu SGlu Ala Val Arg Leu Phe Val Glu Trp Leu Lys Asn-NH, [SEQ. ID. NO.

58] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3200.6.

EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Val Glu Phe Leu Lys Asn-NH, [SEQ. ID.

NO. 59] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of 0the product peptide. Electrospray Mass Spectrometry calculated 3143.5.

EXAMPLE 56 Preparation of Compound 56 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe tButylgly Glu Trp Leu Lys Asn-NH 2

[SEQ.

ID. NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry Scalculated 3216.5.

EXAMPLE 57 SPreparation of Compound 57 SAla Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe tButylgly Glu Phe Leu Lys Asn-NH, [SEQ.

ID. NO. 61] The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide 0 norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3159.4.

EXAMPLE 58

L

4 Preparation of Compound 58 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Trp Leu Lys Asn-NH, [SEQ. ID. NO.

62] The above-i-dentified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of Sthe product peptide. Electrospray Mass Spectrometry calculated 3200.6.

EXAMPLE 59 Preparation of Compound 59 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Phe Leu Lys Asn-NFH [SEQ. ID. NO.

63] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc- -o protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3143.5.

EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH, (SEQ. ID.

NO. 64] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide 0 norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound I. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3099.5.

EXAMPLE 61 Preparation of Compound 61 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH, [SEQ. ID.

NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3081.4.

EXAMPLE 62 Preparation of Compound 62 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Ala Lys Asn-NH 2 [SEQ. ID.

NO. 66] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized n/ peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3172.5.

EXAMPLE 63 Preparation of Compound 63 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Ala Lys Asn-NH, [SEQ. ID.

NO. 67] The above-identified amidated peptide is assembled on 4- 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (aradient 30% to Solvent B in Solvent A over 30 minutes) cf the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3115.5.

EXAMPLE 64 Preparation of Compound 64 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Ala Asn-NH, [SEQ. ID.

NO. 68] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3157.5.

EXAMPLE Preparation of Compound Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Ala Asn-NH, [SEQ. ID.

NO. 69] The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized 1 peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3100.4.

EXAMPLE 66 Preparation of Compound 66 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Ala-NH, [SEQ. ID.

NO. The above-identified amidated peptide is assembled on 4o 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3171.6.

EXAMPLE 67 SPreparation of Compound 67 Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Ala-NH 2 [SEQ.

ID.

NO. 71] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3114.5.

EXAMPLE 68 Preparation of Comound 68 Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro-NH, [SEQ. ID. NO. 72] The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4033.5.

EXAMPLE 69 Preparation of Compound 69 His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe lie Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro-NH, [SEQ. ID. NO. 73] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide iu norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3984.4.

EXAMPLE 1 Preparation of Compound His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro-NH, (SEQ. ID. NO. 74] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4016.5.

EXAMPLE 71 Preparation of Compound 71 His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro-NH, [SEQ. ID. NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry D calculated 3861.3.

EXAMPLE 72

\O

N Preparation of Compound 72 b Ala Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gin Leu Glu Glu \O Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser O Ser Gly Ala Pro-NH, [SEQ. ID. NO. 76] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3746.1.

EXAMPLE 73 Preparation of Compound 73 Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH, [SEQ. ID. NO. 77] \O ID

O

C 4 I0

ON

eq ^sO 1 O in The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3742.1.

EXAMPLE 74 Preparation of Compound 74 His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH [SEQ. ID. NO. 78] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3693.1.

EXAMPLE Preparation of Compound His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly-NH 2 [SEQ. ID. NO. 79] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide '0 norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3751.2.

EXAMPLE 76 Preparation of Compound 76 His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser-NH, [SEQ. ID. NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from Sthe resin, deprotected and purified in a similar way to Compound in 1. Used in analysis are Solvent A TFA in water) and C( Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3634.1.

EXAMPLE 77 Preparation of Compound 77 Ala Gly Glu Gly Thr Phe Thr Ser Asp Lej Ser Lys Gin Met Glu Glu I/ Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn Glv Gly Pro Ser- NH, [SEQ. ID. NO. 81] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc- 12o protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3526.9.

EXAMPLE 78 Preparation of Compound 78 His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser-

NH

2 [SEQ. ID. NO. 82] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3477.9.

EXAMPLE 79 Preparation of Compound 79 His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro-NH, [SEQ. ID. NO. 83] 89 The above-identified amidated peptide is assembled on 4- 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide C( norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from 0D the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 0 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3519.9.

EXAMPLE Preparation of Compound His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly-NH, [SEQ. ID. NO. 84] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized oA peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3307.7.

EXAMPLE 81 Preparation of Compound 81 Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly-NH, [SEQ. ID.

NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A (0.11 TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (oradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3186.5.

EXAMPLE 82 Preparation of Compound 82 His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly tPro Ser Ser Gly Ala tPro tPro tPro-NH, [SEQ. ID. NO. 86] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound lf 1. Double couplings are required at residues 37,36 and 31. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4121.1.

EXAMPLE 83 Preparation of Compound 83 His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala tPro tPro tPro-NH, [SEQ. ID. NO. 87] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide o2 norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Double couplings are required at residues 37, 36 and 31. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4173.2.

EXAMPLE 84 Preparation of Compound 84 His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMeala Ser Ser Gly Ala NMeala Nmeala-NH, [SEQ. ID. NO. 88] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Double couplings are required at residues 36 and 31. Used in analysis are Solvent A TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent

B

in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3796.1.

0 93 EXAMPLE Preparation of Compound Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu S/ Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly Ala hPro-NH 2 [SEQ. ID. NO. 89]

(N

ND The above-identified amidated peptide is assembled on 4- (3 2 4 '-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. A double coupling is required at residue 31. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3871.1.

EXAMPLE 86 Prepara t ion of Compound 86 His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH, [SEQ. ID. NO. The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc- IN 94 0M protected amino .acids (Applied Biosystems, Inc.), cleaved from gthe resin, deprotected and purified in a similar way to Compound 1. Used in anal -sis are Solvent A TFA in water) and Solvent B (0.11 TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized 0 peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry n calculated 3750.2.

O EXAMPLE 87 Preparation of Compound 87 His Gly Asp Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH, [SEQ. ID. NO. 91] The above-identified amdiated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3408.8.

>1

IN

EXAMPLE 88 Preparation of Compound 88 Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH, [SEQ. ID. NO. 92] The above-identified amidated peptide is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4120.6.

EXAMPLE 89 Preparation of Compound 89 Ala Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH 2 [SEQ. ID. NO. 93] The above-identified amidated peptide is assembled on 4- 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide (N norleucine MBHA .resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from.

the resin, deprotected and purified in a similar way to Compound 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of C\ the product peptide. Electrospray Mass Spectrometry 4\ calculated 4005.5.

EXAMPLE Preparation of Peptide having SEO. ID. NO. Compound No. 90, 4 -imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys-NHCoctanoyl Asn-NH 2 [SEQ. ID. NO. 95), is A assembled on 4 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NH'octanoyl acid is used for coupling at position 27. Instead of using a protected amino acid for the final coupling at position 1, 4 -imidazolylpropionic acid is coupled directly to the N-terminus of residues 2-28 on the resin. Used in analysis are Solvent A TFA in water) and Solvent B TFA in CAN). Analytical RP-HPLC (gradient A' to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3361.7 EXAMPLE 91 Preparation of Peptide having SEQ. ID. NO. 96 Compound No. 91, 4 -imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys-NHoctanoyl Asn-NH, [SEQ. ID. NO. 96], is assembled on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NHCoctanoyl acid is used for coupling at position 27. Instead of using a protected amino acid for the final coupling at position 1, 4-imidazolylpropionic acid is coupled directly to the N-terminus of residues 2-28 on the resin. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3304.6 EXAMPLE 92 Preparation of Peptide having SEO. ID. NO. 97 Compound No. 92, 4 -imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys-NH'octanoyl Asn Gly Gly-NH, [SEQ. ID. NO.

97], is assembled on 4 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 (CI mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a I similar way to Example 1. Fmoc-Lys-NH t octanoyl acid is used for 4 coupling at position 27. Instead of using a protected amino acid for the final coupling at position 1, 4 -imidazolylpropionic acid IN is coupled directly to the N-terminus of residues 2-30 on the t (0 resin. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3475.8 EXAMPLE 93 Preparation of Peptide having SEQ. ID. NO. 98 Compound No. 93, 4 -imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys-NHEoctanoyl Asn Gly Gly-NH, [SEQ. ID. NO.

98], is assembled on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a J similar way to Example 1. Fmoc-Lys-NH'octanoyl acid is used for coupling at position 27. Instead of using a protected amino acid for the final coupling at position 1, 4 -imidazolylpropionic acid is coupled directly to the N-terminus of residues 2-30 on the resin. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3418.7 EXAMPLE 94 Preparation of Peptide having SEO. ID. NO. 99 Compound No. 94, 4 -imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Asn Lys-NHoctanoyl-NH, [SEQ. ID. NO. 99], is assembled on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys -NHoctanoyl acid is used for the initial coupling onto the resin at position 28. Instead of using a protected amino acid for the final coupling at position 1, 4imidazolylpropionic acid is coupled directly to the N-terminus of protected residues 2-28 on the resin. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 3361.7 EXAMPLE Preparation of Peptide having SEO. ID. NO. 100 C( Compound No. 95, 4 -imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe r- Ile Glu Phe Leu Asn Lys-NHoctanoyl-NH 2 [SEQ. ID. NO. 100], is V3 assembled on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) I using Fmoc-protected amino acids (Applied Biosystems, Inc.), 6 cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NH'octanoyl acid is used for the initial coupling onto the resin at position 28. Instead of using a protected amino acid for the final coupling at position 1, 4imidazolylpropionic acid is coupled directly to the N-terminus of residues 2-28 on the resin. Used in analysis are Solvent A j TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 3304.6 EXAMPLE 96 Preparation of Peptide having SEO. ID. NO. 101 Compound 96, 4 -imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Asn Lys-NH'octanoyl Gly Gly-NH, [SEQ. ID. NO. 101], b is assembled on 4 2 '-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NH'octanoyl acid is used for coupling at position 28. Instead of using a protected amino acid q for the final coupling at position i, 4 -imidazolylpropionic acid is coupled directly to the N-terminus of protected residues 2-30 on the resin. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3475.8 EXAMPLE 97 Preparation of Peptide having SEQ. ID. NO. 102 Compound No. 97, 4 -imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Asn Lys-NHoctanoyl Gly Gly-NH 2 [SEQ. ID. NO.

102], is assembled on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 Co mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NH'octanoyl acid is used for coupling at position 28. Instead of using protected His for the final coupling at position i, 4 -imidazolylpropionic acid is cr coupled directly to the N-terminus of residues 2-30 on the resin. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 102 Solvent B in.Solvent A over 30 minutes) of the lyophilized 0 peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry C calculated 3418.7 I ND EXAMPLE 98 Preparation of Peptide having SEO. ID. NO. 103

(N

M\ Compound No. 98, Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys-NHCoctanoyl Asn-NH, [SEQ. ID. NO. 103], is assembled on 4- '0 (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NH t octanoyl acid is used for coupling at position 27. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry 0 calculated 3334.6 EXAMPLE 99 Preparation of Peptide having SEO. ID. NO. 104 Compound No. 99, Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys-NH'octanoyl Asn-NH, [SEQ. ID. NO. 104], is assembled on 4- 103 S(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide Snorleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from Sthe resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NH'octanoyl acid is used for coupling at position 27. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of 0 the product peptide. Electrospray Mass Spectrometry calculated 3277.6 EXAMPLE 100 Preoaration of Peotide having SEO. ID. NO. 105 Compound No. 100, Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys-NHoctanoyl Asn Gly Gly-NH, [SEQ. ID. NO. 105], is assembled on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NHoctanoyl acid is used for coupling at position 27. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized .A peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3442.8 104 EXAMPLE 101 Preparation of Peptide havina SEO. ID. NO. 106 Compound No. 101, Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys-NH'octanoyl Asn Gly Gly-NH, [SEQ. ID. NO. 106], is assembled on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example '0 1. Fmoc-Lys-NHoctanoyl acid is used for coupling at position 27. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3391.7 EXAMPLE 102 Preparation of PeDtide having SEQ. ID. NO. 107 Compound No. 102, Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu 0 Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Asn Lys-NHcoctanoyl-NH, [SEQ. ID. NO. 107], is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 105 1. Fmoc-Lys-NH'octanoyl acid is used for the initial coupling onto the resin at position 28. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 3334.6 EXAMPLE 103 Preparation of Peptide having SEO. ID. NO. 108 Compound No. 103, Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Asn Lys-NH t octanoyl-NH, [SEQ. ID. NO. 108], is assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NHoctanoyl acid is used for the initial coupling onto the resin at position 28. Used in analysis are Solvent

A

TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 3277.6

IO

0 106 EXAMPLE 104 Preparation of Peptide having SEO. ID. NO. 109 (C Compound No. 104, Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu C Asn Lys-NHcoctanoyl Gly Gly-NH, [SEQ. ID. NO. 1091, is assembled VS on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from Sthe resin, deprotected and purified in a similar way to Example 0 1. Fmoc-Lys-NH'octanoyl acid is used for coupling at position 28. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3442.8 EXAMPLE 105 Preparation of Peptide having SEQ. ID. NO. 110 Compound No. 105, Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu 0 Ser Lys Gin Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Asn Lys-NHoctanoyl Gly Gly-NH, [SEQ. ID. NO. 110], is assembled on 4-(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmocprotected amino acids (Applied Biosystems, Inc.), cleaved from 21 the resin, deprotected and purified in a similar way to Example 1. Fmoc-Lys-NHroctanoyl acid is used for coupling at position 107 28. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 3391.7 EXAMPLE 106 Preparation of C-terminal carboxylic acid peptides corresponding to the above C-terminal amide sequences for Compounds 1-67, 73- 79, 80-81, 86-89 and 90-105.

C-terminal carboxylic acid peptides corresponding to amidated Compounds 1-67, 73-79, 80-81, 86-89 and 90-105 are assembled on the so called Wang resin (p-alkoxybenzylalacohol r resin (Bachem, 0.54 mmole/g)) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to that described in Example 1.

Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized '0 peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry provides an experimentally determined Q EXAMPLE 107 (1 Preparation of C-terminal carboxvlic acid peptides corresponding to the above C-terminal amide sequences for Compounds 68-72, 79 and 82-85.

IO

I C-terminal carboxylic acid eptides corresponding to amidated Compounds 68-72, 79 and 82-85 are assembled on the 2- IO chlorotritylchloride resin (200-400 mesh), 2% DVB (Novabiochem, C 0.4-1.0 mmole/g)) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to that described in Example 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry provides an experimentally determined EXAMPLES A TO E Reagents Used GLP-1[7-36]NH, (GLP-1) was purchased from Bachem (Torrance, AO CA). All other peptides were prepared using synthesis methods such as those described therein. All chemicals were of the highest commercial grade. The cAMP SPA immunoassay was purchased from Amersham. The radioligands were purchased from New England Nuclear (Boston, MA). RINm5f cells (American Type Tissue Collection, Rockville, MD) were grown in DME/F12 medium containing 10% fetal bovine serum and 2mM L-glutamine. Cells 109 were grown at 37 0 C and 5% C0,/95% humidified air and medium was replaced every 2 to 3 days. Cells were grown to confluence then harvested and homogenized using on a Polytron homogenizer. Cell homogenates were stored frozen at -70 0 C until used.

1/ EXAMPLE A GLP-1 Receptor Binding Studies Receptor binding was assessed by measuring displacement of 1 IGLP-1 or 25 IJexendin(9-39) from RINm5f membranes. Assay buffer contained 5 pg/ml bestatin, 1 pg/ml phosphoramidon, 1 fo mg/ml bovine serum albumin (fraction 1 mg/ml bacitracin, and 1 mM MgC1, in 20 mM HEPES, pH 7.4. To measure binding, 30 pg membrane protein (Bradford protein assay) was resuspended in 200 pl assay buffer and incubated with 60 pM ['2I]GLP-1 or I)exendin(9-39) and unlabeled peptides for 120 minutes at 23 0 C in 96 well plates (Nagle Nunc, Rochester, NY). Incubations were terminated by rapid filtration with cold phosphatebuffered saline, pH 7.4, through polyethyleneimine-treated GF/B glass fiber filters (Wallac Inc., Gaithersburg, MD) using a Tomtec Mach II plate harvester (Wallac Inc., Gaithersburg,

MD).

0 Filters were dried, combined with scintillant, and radioactivity determined in a Betaplate liquid scintillant counter (Wallac Inc.).

Peptide samples were run in the assay as duplicate points at 6 dilutions over a concentration range of 10- 6 M to 10" 2 M to generate response curves. The biological activity of a sample is expressed as an IC,, value, calculated from the raw data using an iterative curve-fitting program using a 4 -parameter logistic equation (PrizmTM, GraphPAD Software). The results are Sshown in Table I.

TABLE I SCompound IC,,(nM) Exendin-4 [SEQ. ID. NO. 2] 0.7 Compound 1 [SEQ. ID. NO. 5] 26.1 Compound 2 [SEQ. ID. NO. 6] 14.42 Compound 3 [SEQ. ID. NO. 7] 41.65 Compound 4 [SEQ. ID. NO. 8] 4.96 EXAMPLE B Cyclase Activation Study Assay buffer contained 10 pM GTP, 0.75 mM ATP, 2.5 mM MgCl 2 0.5mM phosphocreatine, 12.5 U/ml creatine kinase, 0.4 mg/ml aprotinin, 1 pM IBMX in 50 mM HEPES, pH 7.4. Membranes and peptides were combined in 100 ml of assay buffer in 96 well filter-bottom plates (Millipore Corp., Bedford, MA). After minutes incubation at 37 0 C, the assay was terminated by transfer of supernatant by filtration into a fresh 96 well plate using a Millipore vacuum manifold. Supernatant cAMP contents were quantitated by SPA immunoassay.

Peptide samples were run in the assay as triplicate points at 7 dilutions over a concentration range of 10-'M to 10- 2 M to generate response curves. The biological activity of a particular sample was expressed as an EC, 0 value, calculated as described above. Results are tabulated in Table II.

TABLE II Compound EC (nM) Exendin-4 [SEQ. ID. NO. 2] 0.23 Compound 1 [SEQ. ID. NO. 5] >1,000 Compound 2 [SEQ. ID. NO. 6] >10,000 Compound 3 [SEQ. ID. NO. 7] >10,000 Compound 4 [SEQ. ID. NO. 8] >10,000 0 EXAMPLE

C

Determination of Blood Glucose Levels in db/db Mice CS7BLKS/J-m-db mice at least 3 months of ace were utilized for the study. The mice were obtained from The Jackson Laboratory and allowed to acclimate for a- least one week before use. Mice were housed in groups of ten at 22° 0 C with a 12:12 light:dark cycle, with lights on at 6 a.m.

All animals were deprived of food for 2 hours before taking baseline blood samples. Approximately 70 pl of blood was drawn from each mouse via eye puncture, after a light anesthesia with metophane. After collecting baseline blood samples, to measure plasma glucose concentrations, all animals receive subcutaneous injections of either vehicle (10.9% NaC1), exendin-4 or test compound (1 pg) in vehicle. Blood samples were drawn again, using the same procedure, after exactly one hour from the da injections, and plasma glucose concentrations were measured.

112 For each animal, the change in plasma value, from baseline value, was calculated. The percent decrease in plama Sglucose after one hour is shown in Table III.

?1 TABLE III 0 Test Compound drop in glucose Exendin-4 [SEQ. ID. NO. 2] 39% (n 78) Compound 1 [SEQ. ID. NO. 5] 40% (n 4) Compound 2 [SEQ. ID. NO. 6] 41% (n Compound 3 [SEQ. ID. NO. 7] 32% (n Compound 4 [SEQ. ID. NO. 8] 42% (n EXAMPLE D Dose Response Determination of Blood Glucose Levels in db/db Mice C57BLKS/J-m-db/db mice, at least 3 months of age were utilized for the study. The mice were obtained from The Jackson Laboratory and allowed to acclimate for at least one week before use. Mice were housed in groups of ten at 22 0 C 1°C with a 12:12 light:dark cycle, with lights on at 6 a.m.

All animals were deprived of food for 2 hours before taking baseline blood samples. Approximately 70 pl of blood was drawn from each mouse via eye puncture, after a light anesthesia with metophane. After collecting baseline blood samples, to measure plasma glucose concentrations, all animals receive subcutaneous injections of either vehicle, exendin-4 or test compound in concentrations indicated. Blood samples were drawn again, using 113 the same procedure, after exactly one hour from the injections, and plasma glucose concentrations were measured.

For each animal, the change in plasma value, from baseline value, was calculated and a dose dependent relationship was evaluated using Graphpad PrizmT m software.

Figure 5 depicts the effects of varying doses of exendin-4 [SEQ. ID. NO. 2] and Compound 1 [SEQ. ID. NO. 5] on plasma glucose levels. Exendin-4 had an ED, 0 of 0.01 jpg per mouse and Compound 1 had an ED,, of 0.42 pg per mouse.

0 EXAMPLE

E

Gastric Emptying The following study was carried out to examine the effects of exendin-4 and an exendin agonist compound of the present invention on gastric emptying in rats. This experiment followed a modification of the method of Scarpignato, et al., Arch. Int.

Pharmacodyn. Ther. 246:286-94, 1980.

Male Harlan Sprague Dawley (HSD) rats were used. All animals were housed at 22.7 0.8 C in a 12:12 hour light:dark cycle (experiments being performed during the light cycle) and were fed and watered ad libitum (Diet LM-485, Teklad, Madison, WI). Exendin-4 was synthesized according to standard peptide synthesis methods. The preparation of Compound 1 [SEQ. ID. NO.

is described in Example 1.

The determination of gastric emptying by the method described below was performed after a fast of -20 hours to ensure that the stomach contained no chyme that would interfere with spectrophotometric absorbance measurements.

Conscious rats received by gavage, 1.5ml of an acaloric gel containing 1.5% methyl cellulose (M-0262, Sigma Chemical Co, St Louis, MO) and 0.05% phenol red indicator. Twenty minutes after gavage, rats were anesthetized using 5% halothane, the stomach I exposed and clamped at the pyloric and lower esophageal N sphincters using artery forceps, removed and opened into an alkaline solution which was made up to a fixed volume. Stomach Scontent was derived from the intensity of the phenol red in the I alkaline solution, measured by absorbance at a wavelength of S' 560 nm. In separate experiments on 7 rats, the stomach and small intestine were both excised and opened into an alkaline solution. The quantity of phenol red that could be recovered from the upper gastrointestinal tract within 20 minutes of gavage was 89+4%; dye which appeared to bind irrecoverably to the gut luminal surface may have accounted for the balance. To account for a maximal dye recovery of less than 100%, percent of stomach contents remaining after 20 min were expressed as a fraction of the gastric contents recovered from control rats sacrificed immediately after gavage in the same experiment.

Percent gastric contents remaining (absorbance at min)/(absorbance at 0 mm) x 100.

In baseline studies, with no drug treatment, gastric emptying over 20 min was determined. In dose-response studies, rats were treated with 0.01, 0.1, 0.3, 1, 10 and 100 pg of 2< exendin-4, and 0.1, 0.3, 1, 10 and 100 pg of Compound 1 [SEQ.

ID. NO. The results, shown in Figure 6, demonstrate that the exendin agonists, exendin-4 and Compound 1, are potent 115 inhibitors of gastric emptying. The EC, for exendin-4 was 0.27 [Lg. The EC5 0 for Compound 1 was 55. 9 pg.

Claims

116- The claims defining the invention are as follows: 1 A peptide having the amino acid sequence: His Gly Ala Ala Xaa 5 Xaa6 Xaa 7 Xaa 8 Ala XaajO Ser Lys Glu Xaa 14 Glu Glu Glu Ala Val Arg Leu Xaa 22 Xaa 23 Xaa 24 Xaa 25 Leu Lys Asn Z 1 wherein is Ala or Thr; Xaa 6 is Phe or naphthylalanine; Xaa 7 is Thr or Ser; Xaa8 is Ser or Thr; XaajO is Leu, Ile, Val, pentylglycine or Met; Xaa 14 is Leu, pentyiglycine or Met; Xaa 22 is Phe or naphthylalanine; Xaa 23 is Ile or Val; Xaa 24 is Glu or Asp; Xaa 25 is Trp or Phe; Z, is -OH -Nil 2 Gly -Z 2 Gly Gly -Z 2 Gly Gly Xaa 3 1 -Z 2 Gly Gly Xaa 31 Ser -Z 2 Gly Gly Xaa 31 Ser Ser -Z 2 Gly Gly Xaa 31 Ser Ser Gly -Z 2 Gly Gly Xaa 31 Ser Ser Gly Ala -Z 2 Gly Gly Xaa 3 1 Ser Ser Gly Ala Xaa 36 -Z 2 Gly Gly Xaa 3 l Ser Ser Gly Ala Xaa 36 Xaa 37 -Z 2 Gly Gly Xaa 31 Scr Scr Gly Ala Xaa 36 Xaa 37 Xaa 38 -Z 2 Gly Gly Xaa 3 1 Ser Ser Gly Ala Xaa 36 Xaa 37 Xaa 3 8 Ser-Z 2 wherein Xaa 31 Xaa 36 Xaa 37 and Xaa 3 8 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine; and Z 2 is -OH or -Nil 2 and pharmaceutically acceptable salts, thereof. 2. The peptide of claim 1, wherein Xaa 9 is Ala. 3. The peptide of claim 1, wherein Z, is NIL 2 R:\LI BAJO756I .docijp -117- 4. The peptide of claim 1, wherein Z 2 is NH 2 A peptide having the amino acid sequence: Xaaj Gly Xaa 3 Ala Xaa 5 Xaa6s Xaa 7 Xaa 8 Ala Xaa 10 Xaa 1 1 Xaa. 12 Xaa 13 Xaa 14 Xaa 15 Xaa 16 Xaa 17 Ala Xaal 9 Xaa 2 0 Xaa 2 1 Xaa 22 Xaa 23 Xaa 24 Xaa 25 Xaa 26 X 1 -ZI; wherein Xaa 1 is His or 4-imidazopropionyl; Xaa 3 is Ala, Asp or Glu; Xaa 5 is Ala or Thr; Xaa( 6 is Phe or naphthylalanine; Xaa 7 is Thr or Ser; Xaag is Ala, Ser or Thr; XaajO is Ala, Leu, Ile, Val, pentyiglycine or Met; Xaa 1 is Ala or Ser; Xaa 12 is Ala or Lys; Xaa 13 is Ala or Gin; Xaa 14 is Leu, pentyiglycine or Met; Xaa 15 is Ala or Glu; Xaa 16 is Ala or Glu; Xaa 17 is Ala or Glu; Xaa 19 is Ala or Val; Xaa 2 0 is Ala or Mrg; Xaa 2 1 is Lys-NIP-R where R is Lys, Arg, Cj-Cj 0 straight chain or branched alkanoyl or cycloalkylalkanoyl; Xaa 22 is Phe or naphthylalanine; Xaa 23 is le or Val; Xaa 24 is Ala, Glu or Asp; Xaa 2 5 is Trp or Phe; Xaa 26 is Ala or Leu; X, Lys Asn, Asn Lys, Lys-N]HP-R Asn, Asn Lys-NH 6 Lys-NWH-R Ala, Ala Lys-NHE-R, where R is Lys, Mg, C 1 -C 10 straigh chain or branched alkanoyl or cycloalkylalkanoyl; Z, is -OH -Ni- 2 Gly -Z 2 Gly Gly -Z 2 RAUiBA10756I 1,dockjp -118- Gly Gly Xaa 31 -Z 2 Gly Gly Xaa 31 Ser -Z 2 Gly Gly Xaa 31 Ser Ser -Z2 Gly Gly Xaa 31 Ser Ser Gly -Z2 Gly Gly Xaa 31 Ser Ser Gly Ala -Z2 Gly Gly Xaa 31 Ser Ser Gly Ala Xaa 36 -Z 2 Gly Gly Xaa 31 Ser Ser Gly Ala Xaa 36 Xaa 37 -Z2 Gly Gly Xaa 31 Ser Ser Gly Ala Xaa 36 Xaa 37 Xaa 3 8-Z 2 Gly Gly Xaa 31 Ser Ser Gly Ala Xaa 36 Xaa 37 Xaa 3 8 Ser-Z 2 wherein Xaa 3 1 Xaa 36 Xaa 37 and Xaa 3 g are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine; and Z 2 is -OH or -NH 2 provided that only one of Xaa 3 Xaas, Xaas, Xaaio, Xaai l, Xaa 12 Xaa 13 Xaa 15 Xaai 6 Xaa 17 Xaa 19 Xaa 2 0 Xaa 2 4 and Xaa 26 is Ala; and pharmaceutically acceptable salts, thereof. 6. The peptide of claim 5, wherein Xaal is His. 7. The peptide of claim 5, wherein Xaa is 4-imidazopropionyl. 8. The peptide of claim 5, wherein Xaa 3 is Ala. 9. The peptide of claim 5, wherein Zi is NH 2 10 The peptide of claim 5, wherein Z 2 is NH 2 11. A method for the treatment of diabetes mellitus comprising administering a therapeutically effective amount of a compound of any one of claims 1-10. 12. The method according to claim 11, wherein the diabetes mellitus is type I diabetes mellitus. 13. The method according to claim 11, wherein the diabetes mellitus is type II diabetes mellitus. 14. The use of any one of the compounds of claims 1-10 in the manufacture of a medicament for the treatment of diabetes mellitus. The use according to claim 14, wherein the diabetes mellitus is type I diabetes mellitus. 16. The use according to claim 14, wherein the diabetes mellitus is type II diabetes mellitus. 17. The method according to any one of claims 11-13, further comprising administration of a therapeutically effective amount of insulin. [R \LIBA]07561 doc jip -119- 18. The use of any one of claims 14-16, wherein said medicament further comprises insulin. 19. A method for treating hyperglycemia comprising administering a therapeutically effective amount of a compound of any one of claims 1-10. 20. The use of the compound of any one of claims 1-10 for the manufacture of a medicament for the treatment of hyperglycemia. Dated 29 September, 2006 Amylin Pharmaceuticals, Inc. Patent Attorneys for the Applicant/Nominated Person 1o SPRUSON FERGUSON [R \LIBA]07561doc jp