CN1809372A - Melanocortin recptor 4(MC4) agonists and their uses - Google Patents
Melanocortin recptor 4(MC4) agonists and their uses Download PDFInfo
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- CN1809372A CN1809372A CN 200480017178 CN200480017178A CN1809372A CN 1809372 A CN1809372 A CN 1809372A CN 200480017178 CN200480017178 CN 200480017178 CN 200480017178 A CN200480017178 A CN 200480017178A CN 1809372 A CN1809372 A CN 1809372A
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Abstract
The present invention relates to peptide agonists of the MC4 receptor, and as such are useful in the treatment of disorders responsive to the activation of this receptor, such as obesity, diabetes mellitus and male and/or female sexual dysfunction.
Description
The present invention relates to the peptide agonists of MC4 receptor and relate to it be used for the treatment of to activating the purposes of the aitiogenic disease of this receptor such as obesity, diabetes and male and/or female sexual dysfunction.
The pre-prohormone of a 31-36kDa of proopiomelanocortin (POMC) gene code derives seven kinds of sophisticated peptide hormones by it.The processing of POMC is carried out in tissue-specific mode, produces four kinds of different melanocortin peptides: thyroliberin (ACTH), α-melanotropin (α-MSH), β-MSH and γ-MSH.
Identify five kinds of melanocortin receptors so far and be called MC1, MC2, MC3, MC4 and MC5 here.The main endogenic ligand of MC1 is α-MSH, and is relevant with pigmentation.The main endogenic ligand of MC2 is ACTH, generates relevant with steroid.MC2 completely different in other melanocortin receptor and think except with the reaction of ACTH or its analog, can not with endogenous or synthetic MSH reaction (Schi_th etc., Life Sciences 59 (10): 797-801 page or leaf, 1996).It is believed that it is α-MSH and ACTH that MC5 has two kinds of main parts, and relevant with the secretion of external secretion Amenand sebaceous gland lipid.
Comprise the gene and the pharmacy data that obtain from rodent and people, different evidences support the MC4 receptors particularly to regulate effect in food intake and the metabolism regulating energy homeostasis.The distribution of MC4 receptor in brain and trophic behavior to melanocortin mediation show that the zone presents well relevant (MacNeil etc., Eur.J.Pharm.440 (2-3): 141-57,2002) in the brain of hypersensitivity.And, it is believed that the MC4 receptor participates in regulating body weight significantly, this point can by Mc4r-/-fat these facts of people of mice obesity and melanocortin receptor gene mutation are as evidence.Thereby the MC4 receptor stimulating agent can useful treatment for obesity.
The research and development of the selectivity peptide agonists of casting skin matter hormone receptor followed closely multiple casting skin matter hormone receptor hypotype and their identification main part evaluation and carry out.As α-MSH, a kind of 13 amino acid whose peptides are the non-selective agonist that are MC1 and MC3-MC5 to four casting skin matter hormone receptors.NDP α-MSH is more effective a, protease resistant but still is nonselective alpha-MSH analogue.
Derive and the lactams that comes is that MTII is more effective than NDP-α-MSH in vivo from 4-10 the fragment of α-NDP-MSH, but it is nonselective.Replace the D-phenylalanine with D-(2 ') NaI and produce one MC3 and MC4 had the antagonist of high-affinity in MTII, this antagonist is the agonist of MC1 and MC5 receptor.This peptide is called as SHU9119.
Though the many peptides through the disulphide bridges cyclisation are MC4 receptor stimulating agents, several MC4 of being receptor antagonists are arranged and the MC3 receptor is had medium selectivity.Peptide HS014 is the partial agonist of MC1 and MC5 receptor, and peptide HSO24 does not show agonist activity to MC1 and MC3 receptor.In addition, PCT publication number WO 00/35952 discloses some and has had the peptide through the disulphide bridges cyclisation of MC4 agonist effectiveness.
Although the progress that above having had and other places are discussed still continues to have the MC4 agonist of pharmaceutically ideal selectivity, effectiveness and effect to be used as the medicine especially for treatment of obesity.Ideal especially MC4 agonist is the MC4 agonist with ideal clinically pharmacy and safety features.
Obesity
Obesity particularly UBSO disease be the U.S. and global one generally and very serious health problem.According to nearest statistics, American population more than 25% and 27% Canadian crowd are overweight.Kuczmarski, Amer.J.of Clin.Nutr.55 volume: 495S-502S, 1992; Can.Med.Assn.J. such as Reeder, 23 volumes: 226-33 page or leaf, 1992.UBSO disease is the strongest risk factor of known type ii diabetes, and is the strong risk factor of cardiovascular disease and cancer equally.Estimate that recently the whole world is used for the medical expense Shi $150 of obesity, 000,000,000.So serious U.S. sanitary general administration has initiated to fight with the ever-increasing obesity that spreads in American society to such an extent as to this problem has become.
Male and/or female sexual dysfunction
As if the MC4 receptor works in other physiological function equally, promptly controls grooming behavior, erection and blood pressure." female sexual dysfunction " includes but not limited to as lacking libido and relevant diseases such as sexual excitation obstacle, orgasm inhibition, lubricated difficulty and vulvismus.
" erection disturbance " is to comprise that boar fails to finish erection, ejaculate or fail to finish both diseases.The disorder of erection function shape comprises can not finish or keep erection, ejaculation failure, premature ejaculation and can not acquired climax.The increase of erection disturbance is usually relevant with the age and usually cause by physiological decease or as the side effect of Drug therapy.Be usually used in describing this general disease during term " sexual impotence ".Found synthetic melanocortin-4 receptor agonists to be used for causing (the Wessells etc. that erect male with psychological erection disturbance, " Synthetic Melanotropic PeptideInitiates Erections in Men With Psychogenic Erectile Dysfunction:Double-Blind; Placebo Controlled Crossover Study " J.Urol., 160 volumes: 389-93 page or leaf, 1998).The activation of the melanocortin receptor of brain seems to cause the normal stimulus of libido.The evidence that the MC4 receptor relates to male and/or female sexual dysfunction has a detailed description in WO 00/74670.
Diabetes
Diabetes are a kind of wherein because it is the ability that is used for being stored in muscle and hepatocyte glycogen with conversion of glucose that mammal has what weaken, and the ability that mammal is regulated glucose level in the blood is weakened.In type i diabetes, the ability of this storage glucose that weakens is produced to reduce by insulin and causes." type ii diabetes " or " noninsulin dependent diabetes " is a kind of diabetes of form (NIDDM), and these diabetes are owing to be the diabetes that in muscle, liver and the fatty tissue the remarkable resistance of the stimulation of glucose and lipid metabolism or regulating and controlling effect caused to insulin at main insulin sensitivity tissue.When this resistance to insulin response causes glucose uptake, oxidation and the storage in muscle inadequate insulin activation and in fatty tissue in steatolysis and the liver glucose generate and during secretion inadequate insulin suppress.When these cells become insulin is desensitized, health is attempted to compensate by producing unusual high insulin level, thereby causes hyperinsulinemia (hyperinsulemia).Hyperinsulinemia is relevant with the body weight of hypertension and rising.Since insulin participates in promoting cell cellular uptake glucose, aminoacid and triglyceride from blood of insulin sensitivity, insensitive performance to insulin causes that triglyceride and LDL level rise, and the level that triglyceride and LDL rise is the risk factor in the cardiovascular disease.Comprise hyperinsulinemia, be associated with hypertension, these symptoms combinations of the LDL of the triglyceride of the body weight of rising, rising and rising are called as X syndrome.
The applicant has had been found that the MC4 receptor is had beyond thought high-affinity and to MC4 receptor rather than other melanocortin receptor hypotype chemical compound selectively.
The present invention relates to the chemical compound represented by following structural formula I:
And officinal salt, wherein
W is Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya or shortage.
R
1Be-H ,-C (O) CH
3,-C (O) (CH
2)
1-4CH
3,-C (O) (CH
2)
1-4NHC (NH) NH
2, Tyr-β Arg-, Ac-Tyr-β-hArg-, glucose acidic group (gluconoyl)-Tyr-Arg-, Ac-diamino bytyry-, Ac-two alanyl-, N-propiono, N-bytyry-, the N-valeryl-, N-methyl-Tyr-Arg-, N-glutaryl-Tyr-Arg-, N-succinyl-Tyr-Arg-, R
6-SO
2NHC (O) CH
2CH
2C (O)-, R
6-SO
2NHC (O) CH
2CH
2C (O) Arg-, R
6-SO
2NHCH
2CH
2CH
2C (O)-, C
3-C
7Naphthene base carbonyl, phenyl sulfonyl, C
8-C
14Bicyclic aryl sulfonyl, phenyl-(CH
2)
qC (O)-, C
8-C
14Bicyclic aryl-(CH
2)
qC (O)-,
Or
Wherein
R
2Be-H ,-NH
2,-NHC (O) CH
3,-NHC (O) (CH
2)
1-4CH
3,
-NH-TyrC (O) CH
3, R
6SO
2NH-, Ac-Cya-NH-, Tyr-NH-, HO-(C
6H
5)-CH
2CH
2C (O) NH-or CH
3-(C
6H
5)-C (O) CH
2CH
2C (O) NH-;
R
3Be C
1-C
4Straight or branched alkyl, NH
2-CH
2-(CH
2)
q-, HO-CH
2-, (CH
3)
2CHNH (CH
2)
4-, R
6(CH
2)
q-, R
6SO
2NH-, Ser, Ile,
Q is 0,1,2 or 3;
R
6Be phenyl or C
8-C
14Bicyclic aryl;
M is 1 or 2;
N is 1,2,3 or 4;
R
9Be (CH
2)
pOr (CH
3)
2C-;
P is 1 or 2;
R
10Be NH-or disappearance;
R
7Be randomly to use R
4The 5-that replaces or 6-unit's heteroaryl or 5-or 6-unit hetero-aromatic ring;
R
4Be H, C
1-C
4Straight or branched alkyl, phenyl, benzyl or (C
6H
5)-CH
2-O-CH
2-;
R
8The benzyl ring or the cyclohexyl that are phenyl, randomly replace with X;
X is H, Cl, F, Br, methyl or methoxy;
R
11Be-C (O) or-CH
2
R
5Be-NH
2,-OH, glycinol (glycinol), NH
2-Pro-Ser-, NH
2-Pro-Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-,-Ser alcohol ,-Ser-Pro alcohol ,-Lys-Pro alcohol, HOCH
2CH
2-O-CH
2CH
2NH-, NH
2-Phe-Arg-, NH
2-Glu-, NH
2CH
2RCH
2NH-, RHN-or RO-, wherein R is C
1-C
4The straight or branched alkyl; And
L is-S-S-or-S-CH
2-S-.
In a preferred embodiment, the present invention relates to the chemical compound represented by following structural formula II:
And officinal salt, wherein
W is singly-bound, Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp or Phe;
R
1Be-H ,-C (O) CH
3,-C (O) (CH
2)
1-4CH
3,-C (O) (CH
2)
1-4-NHC (NH) NH
2, Tyr-β Arg, glucose acidic group-Tyr-Arg, Ac-Dab, Ac-Dap, N-succinyl-Tyr-Arg, N-propiono, N-valeryl, N-glutaryl-Tyr-Arg, N-bytyry,
R
2Be-H ,-NH
2,-NHC (O) CH
3,-NHC (O) (CH
2)
1-4CH
3Or-NH-TyrC (O) CH
3
R
3Be C
1-C
4Straight or branched alkyl, Ser, Ile,
Q is 0,1,2 or 3;
M is 1 or 2;
P is 1 or 2;
R
4Be H or C
1-C
4The straight or branched alkyl;
X is H, Cl, F, Br, methyl or methoxy; And
R
5Be-NH
2,-OH, glycinol ,-Ser-Pro-NH
2,-Lys-Pro-NH
2,-Ser-OH ,-Ser-Pro-OH ,-Lys-Pro-OH-Arg-Phe-NH
2,-Glu-NH
2,-NHR or-OR, wherein R is C
1-C
4The straight or branched alkyl.
In another embodiment, the present invention relates to the chemical compound represented by structural formula II, condition is especially with R
2=Tyr, R
3=Arg, W=Glu, R
4=H, X=H, m=1, p=1 and R
5=NH
2Combination get rid of.
Another preferred embodiment of the present invention comprises the chemical compound of structural formula II I:
And officinal salt, wherein
W is Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya or disappearance.
R
1Be-H ,-C (O) CH
3,-C (O) (CH
2)
1-4CH
3,-C (O) (CH
2)
1-4NHC (NH) NH
2, Tyr-β Arg-, Ac-Tyr-β-hArg-, glucose acidic group-Tyr-Arg-, Ac-diamino bytyry-, Ac-two alanyl-, N-propiono, N-bytyry-, the N-valeryl-, N-methyl-Tyr-Arg-, N-glutaryl-Tyr-Arg-, N-succinyl-Tyr-Arg-, R
6-SO
2NHC (O) CH
2CH
2C (O)-, R
6-SO
2NHC (O) CH
2CH
2C (O) Arg-, R
6-SO
2NHCH
2CH
2CH
2C (O)-, C
3-C
7Naphthene base carbonyl, phenyl sulfonyl, C
8-C
14Bicyclic aryl sulfonyl, phenyl-(CH
2)
qC (O)-, C
8-C
14Bicyclic aryl-(CH
2)
qC (O)-,
Or
Wherein
R
2Be-H ,-NH
2,-NHC (O) CH
3,-NHC (O) (CH
2)
1-4CH
3,
-NH-TyrC (O) CH
3, R
6SO
2NH-, Ac-Cya-NH-, Tyr-NH-, HO-(C
6H
5)-CH
2CH
2C (O) NH-or CH
3-(C
6H
5)-C (O) CH
2CH
2C (O) NH-;
R
3Be C
1-C
4Straight or branched alkyl, NH
2-CH
2-(CH
2)
q-, HO-CH
2-, (CH
3)
2CHNH (CH
2)
4-, R
6(CH
2)
q-, R
6SO
2NH-, Ser, Ile,
Q is 0,1,2 or 3;
R
6Be phenyl or C
8-C
14Bicyclic aryl;
M is 1 or 2;
P is 1 or 2;
R
4Be H, C
1-C
4Straight or branched alkyl, phenyl, benzyl or (C
6H
5)-CH
2-O-CH
2-;
X is H, Cl, F, Br, methyl or methoxy; And
R
5Be-NH
2,-OH, glycinol, NH
2-Pro-Ser-, NH
2-Pro-Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-,-Ser alcohol ,-Ser-Pro alcohol ,-Lys-Pro alcohol, HOCH
2CH
2-O-CH
2CH
2NH-, NH
2-Phe-Arg-, NH
2-Glu-, NH
2CH
2RCH
2NH-, RHN-or RO-, wherein R is C
1-C
4The straight or branched alkyl;
The chemical compound that in another preferred embodiment of the present invention, relates to structural formula II I, wherein W is a Glu or a singly-bound (i.e. disappearance); R
4Be H or CH
3X is H, Cl, F or Br and R
5Be NH
2Or OH.
An embodiment preferred comprises the chemical compound of structural formula II I, and wherein W is Glu or disappearance; R
1Be H-, Ac-, Arg-, Ac-Arg-or Ac-D-Arg-; M is 1 or 2; P is 1; And R
5Be NH
2Or OH.
Another preferred embodiment of the present invention comprises the chemical compound of structural formula II I, wherein the W disappearance; R
1Be Ac-; M is 2; P is 1; And R
5Be NH
2
Another preferred embodiment of the present invention comprises the chemical compound of structural formula II I, and wherein W is Glu; R
1Be Ac-Arg-; M is 1; P is 1; And R
5Be NH
2
Another preferred embodiment of the present invention comprises the chemical compound of structural formula II I, wherein the W disappearance; R
1Be H; M is 2; P is 1; And R
5Be NH
2
Another preferred embodiment of the present invention comprises the chemical compound of structural formula II I, wherein the W disappearance; R
1Be Arg; M is 2; P is 1; And R
5Be OH.
A most preferred embodiment of the present invention comprises the chemical compound of structural formula II I, and wherein W is Glu; R
1Be Ac-D-Arg-; M is 1; P is 1; And R
5Be NH
2
The present invention includes but be not limited to the chemical compound that those infra tabulars go out:
Specific compound among table 1 the present invention
| Numbering | Title |
| 1 | Ac-encircles [Cys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 2 | Ac-Cya-Arg-encircles [Cys-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 3 | Ac-Tyr-Arg-encircles [Cys-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 4 | Ac-Tyr-Arg-encircles [Cys-Arg-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 5 | Ac-Tyr-Arg-encircles [Cys-Asn-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 6 | Ac-encircles [Cys-Asp-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 7 | Ac-Tyr-Arg-encircles [Cys-Asp-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 8 | Ac-encircles [Cys-Gln-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 9 | Ac-Tyr-Arg-encircles [Cys-Gln-His-D-Phe-Arg-Trp-Cys]-OH |
| 10 | Ac-Tyr-Arg-encircles [Cys-Gln-His-D-Phe-Arg-Trp-Cys]-OMe |
| 11 | Tyr-Arg-encircles [Cys-Gly-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 12 | Ac-Tyr-Arg-encircles [Cys-Gly-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 13 | Ac-Tyr-Arg-encircles [Cys-His-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 14 | Ac-Tyr-Arg-encircles [Cys-Ile-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 15 | Ac-encircles [Cys-Leu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 16 | Ac-encircles [Cys-Lys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| Numbering | Title |
| 17 | N-methyl-Tyr-Arg-encircles [Cys-Met-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 18 | Ac-Tyr-Arg-encircles [Cys-Met-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 19 | Ac-Tyr-Arg-encircles [Cys-Phe-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 20 | Ac-Tyr-Arg-encircles [Cys-Pro-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 21 | Ac-Tyr-Arg-encircles [Cys-Ser-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 22 | Ac-Tyr-Arg-encircles [Cys-Thr-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 23 | Ac-Tyr-Arg-encircles [Cys-Trp-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 24 | Ac-Tyr-Arg-encircles [Cys-Tyr-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 25 | Ac-Tyr-Arg-encircles [Cys-Val-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 26 | Ac-Arg-encircles [Cys-Cya-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 27 | Ac-D-Arg-encircles [Cys-Cya-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 28 | Ac-Tyr-Arg-encircles [Cys-Cya-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 29 | Ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 30 | Ac-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 31 | Ac-encircles [Cys-Glu-His-(4-F-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 32 | Ac-encircles [Cys-Glu-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 33 | Ac-encircles [Cys-Glu-His-(4-Br-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 34 | Ac-encircles [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 35 | Ac-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Lys-Pro-NH 2 |
| 36 | Ac-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser-Pro-NH 2 |
| 37 | N-propiono-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 38 | N-bytyry-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 39 | N-valeryl-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 40 | 3-guanidine radicals propiono-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 41 | 4-guanidine radicals bytyry-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 42 | 5-guanidine radicals valeryl-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 43 | Ac-diaminourea propiono-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 44 | Ac-diaminourea bytyry-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 45 | Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH |
| 46 | D-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 47 | Ac-D-Arg-encircles [Cys-Glu-His-Phe-Arg-Trp-Cys]-NH 2 |
| Numbering | Title |
| 48 | Ac-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 49 | Ac-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH |
| 50 | Ac-Arg-encircles [Cys-Glu-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 51 | Ac-Arg-encircles [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 52 | Ac-D-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 53 | Ac-D-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH |
| 54 | Ac-hArg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 55 | Ac-Cit-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 56 | Ac-Cit-encircles [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 57 | Ac-Leu-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 58 | Ac-Lys-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 59 | Ac-Lys (ipr)-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 60 | Ac-nLeu-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 61 | Ac-nLeu-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser-Pro-NH 2 |
| 62 | Ac-Orn-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 63 | Ac-Val-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 64 | N-(2-naphthalene sulfonyl base)-D-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 65 | N-(2-naphthalene sulfonyl base amino-4-oxo-bytyry)-D-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 66 | 3-(4-hydroxyphenyl) propiono-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 67 | 3-(4-methyl benzoyl) propiono-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 68 | Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 69 | Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH |
| 70 | Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH-(CH 2) 6-NH 2 |
| 71 | Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Glu-NH 2 |
| 72 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 73 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH |
| 74 | N-succinyl-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 75 | N-glutaryl-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| Numbering | Title |
| 76 | N-glutaryl-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH |
| 77 | Glucose acidic group-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 78 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys] alcohol |
| 79 | Ac-Tyr-D-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 80 | Ac-Tyr-Arg-encircles [D-Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 81 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 82 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 83 | Ac-Tyr-Arg-encircles [Cys-Glu-His-(4-F-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 84 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-His)-(4-F-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 85 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-D-His)-(4-F-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 86 | Ac-Tyr-Arg-encircles [Cys-Glu-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 87 | Ac-Arg-encircles [Cys-Glu-(1-Me-His)-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 88 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-D-His)-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 89 | Ac-Tyr-Arg-encircles [Cys-Glu-His-(4-Br-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 90 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-His)-(4-Br-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 91 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-D-His)-(4-Br-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 92 | Ac-Tyr-Arg-encircles [Cys-Glu-His-(4-Me-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 93 | Ac-Tyr-Arg-encircles [Cys-Glu-His-(4-OME-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 94 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-His)-(4-OME-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 95 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-D-His)-(4-OME-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 96 | Ac-Tyr-Arg-encircles [Cys-Glu-(3-Me-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 97 | Ac-Tyr-Arg-encircles [Cys-Glu-(5-Me-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 98 | Ac-Tyr-Arg-encircles [Cys-Glu-(5-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 99 | The Ac-Tyr-Arg-ring [Cys-Glu-(the 1-benzyl-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| Numbering | Title |
| 100 | The Ac-Tyr-Arg-ring [Cys-Glu-(the 1-benzyl-D-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 101 | Ac-Tyr-Arg-encircles [Cys-Glu-(1-Bom-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 102 | The Ac-Tyr-Arg-ring [Cys-Glu-(the 1-pyrazolyl-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 103 | The Ac-Tyr-Arg-ring [Cys-Glu-(4-phenyl-1H-imidazoles-2-base-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 104 | The Ac-Tyr-Arg-ring [Cys-Glu-(4-phenyl-1H-imidazoles-2-base-D-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 105 | The Ac-Tyr-Arg-ring [Cys-Glu-(the 2-pyrazine-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 106 | Ac-Tyr-Arg-encircles [Cys-Glu-(β-(1,2,4-triazole-3-yl))-Ala]-D-Phe-Arg-Trp-Cys]-NH 2 |
| 107 | Ac-Tyr-Arg-encircles [Cys-Glu-(β-(1,2,4-triazole-3-yl))-D-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 108 | Ac-Tyr-Arg-encircles [Cys-Glu-(β-((1-benzyl)-1,2,4-triazole-3-yl))-Ala]-D-Phe-Arg-Trp-Cys]-NH 2 |
| 109 | Ac-Tyr-Arg-encircles [Cys-Glu-(β-((1-benzyl)-1,2,4-triazole-3-yl))-D-Ala]-D-Phe-Arg-Trp-Cys]-NH 2 |
| 110 | The Ac-Tyr-Arg-ring [Cys-Glu-(β-(2-furyl)-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 111 | The Ac-Tyr-Arg-ring [Cys-Glu-(β-(thiophene-2-yl)-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 112 | The Ac-Tyr-Arg-ring [Cys-Glu-(β-(1,3-thiazoles-4-yl)-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 113 | The Ac-Tyr-Arg-ring [Cys-Glu-(β-(pyridin-4-yl)-Ala)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 114 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-glycinol |
| 115 | Ac-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-2-(2-amino ethoxy) ethanol |
| 116 | Ac-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser alcohol |
| 117 | Ac-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH-(CH 2) 6- NH 2 |
| 118 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Glu-NH 2 |
| Numbering | Title |
| 119 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser-Pro-NH 2 |
| 120 | Ac-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser-Pro alcohol |
| 121 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Lys-Pro-NH 2 |
| 122 | Ac-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Lys-Pro alcohol |
| 123 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Arg-Phe-NH 2 |
| 124 | Ac-Tyr-Cit-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 125 | Ac-Tyr-Cit-encircles [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 126 | Ac-Tyr-hArg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 127 | Ac-Tyr-(1-β-hArg)-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 128 | Ac-Tyr-Lys-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 129 | Ac-Tyr-Ser-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 130 | Ac-Tyr-Val-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 131 | N-succinyl-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH |
| 132 | Ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 133 | Ring [hCys-His-D-Phe-Arg-Trp-Cys]-OH |
| 134 | Ring [hCys-His-(4-F-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 135 | Ring [hCys-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 136 | Ac-encircles [hCys-His-Phe-Arg-Trp-Cys]-NH 2 |
| 137 | Ac-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 138 | Ac-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-OH |
| 139 | Ac-encircles [hCys-His-(4-F-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 140 | Ac-encircles [hCys-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH 2 |
| 141 | N-cyclopropane carbonyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 142 | N-Tetramethylene. carbonyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 143 | N-Pentamethylene. carbonyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 144 | N-cyclohexane extraction carbonyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 145 | N-caproyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 146 | N-benzoyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 147 | 4-phenyl bytyry-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 148 | 3-guanidine radicals propiono-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 149 | 5-guanidine radicals valeryl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| Numbering | Title |
| 150 | N-phenyl sulfonyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 151 | N-(2-naphthalene sulfonyl base)-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 152 | N-(4-phenyl sulfonamido-4-oxo-bytyry)-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 153 | Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 154 | D-Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 155 | Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-OH |
| 156 | Arg-encircles [hCys-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 157 | Arg-encircles [hCys-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH 2 |
| 158 | Ac-Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 159 | Ac-Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 160 | Ac-nLeu-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 161 | Phenyl sulfonyl-Gly-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 162 | Tyr-Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 163 | Tyr-Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-OH |
| 164 | Ac-Tyr-Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 165 | Ac-Tyr-Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-OH |
| 166 | Ac-Tyr-Arg-encircles [hCys-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 |
| 167 | The Ac-ring [hCys-His-(β-cyclohexyl-D-Ala)-Arg-Trp-Cys]-NH 2 |
| 168 | Ac-encircles [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 169 | Ac-encircles [hCys-His-(4-Cl-D-Phe)-Arg-Trp-penicillamine]-NH 2 |
| 170 | N-caproyl-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 171 | N-Pentamethylene. carbonyl-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 172 | N-cyclohexane extraction carbonyl-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 173 | N-benzoyl-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 174 | 4-phenyl bytyry-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 175 | N-phenyl sulfonyl-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 176 | (4-benzsulfamide) bytyry-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 177 | Ac-nLeu-encircles [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 178 | N-phenyl sulfonyl-Gly-encircles [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH 2 |
| 179 | Ring [3-sulfo-propiono-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| Numbering | Title |
| 180 | Ring [Cys-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 181 | Ring [Cys-His-(4-F-D-Phe)-Arg-Trp-hCys]-NH 2 |
| 182 | Ring [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH 2 |
| 183 | Ac-encircles [Cys-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 184 | Ac-encircles [Cys-His-(4-F-D-Phe)-Arg-Trp-hCys]-NH 2 |
| 185 | Ac-encircles [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH 2 |
| 186 | Arg-encircles [Cys-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 187 | Arg-encircles [Cys-His-(4-F-D-Phe)-Arg-Trp-hCys]-NH 2 |
| 188 | Arg-encircles [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH 2 |
| 189 | Ac-Arg-encircles [Cys-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 190 | Ac-Arg-encircles [Cys-His-(4-F-D-Phe)-Arg-Trp-hCys]-NH 2 |
| 191 | Ac-Arg-encircles [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH 2 |
| 192 | Ac-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 193 | Ac-encircles [hCys-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 194 | Arg-encircles [hCys-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 195 | Ac-Arg-encircles [hCys-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 196 | Ac-Tyr-Arg-encircles [hCys-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 197 | Ac-Tyr-Arg-encircles [hCys-Glu-His-D-Phe-Arg-Trp-hCys]-NH 2 |
| 198 | Ac-encircles (S-CH 2-S)[Cys-His-D-Phe-Arg-Trp-Cys]-NH 2 |
A preferred embodiment of the present invention comprises chemical compound 48,52,132,137 and No. 155.Preferred one group of chemical compound is made up of 52 and No. 137 chemical compounds.Another preferred embodiment comprises chemical compound No. 137, and it is encircled by compound name Ac-
[hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Expression.A most preferred embodiment of the present invention comprises chemical compound No. 52, and it is encircled by compound name Ac-D-Arg-
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Expression.
In one embodiment, the present invention relates to comprise the pharmaceutical composition of at least one The compounds of this invention or its officinal salt and pharmaceutically suitable carrier.
In another embodiment, the present invention relates to be used for the method for exciting MC4 receptor, described method comprises the chemical compound of being represented by structural formula I, structural formula II or structural formula II I or their pharmaceutical salts of using effective dose to its patient of needs.
In another embodiment, the present invention relates to the method for treatment of obesity in mammal, the step that this method comprises be to needs its structural formula I, structural formula II or the structural formula II I of administration pharmacy effective dose or at least a chemical compound in their pharmaceutical salts.
In another embodiment, the present invention relates to the method for treatment diabetes in mammal, the step that this method comprises is at least a chemical compound in the structural formula I of the administration pharmacy effective dose of needs, structural formula II or structural formula II I or their pharmaceutical salts.
In another embodiment, the present invention relates to treat in mammal the method for male and/or female sexual dysfunction, the step that this method comprises is at least a chemical compound in the structural formula I of its administration pharmacy effective dose of needs, structural formula II or structural formula II I or their pharmaceutical salts.
In another embodiment, the invention further relates to structural formula I, structural formula II or structural formula II I or their pharmaceutical salts purposes as medicine;
In another embodiment, the invention further relates to structural formula I, structural formula II or structural formula II I or their pharmaceutical salts and be used for the treatment of purposes in the obesity drug in production;
In another embodiment, the invention further relates to structural formula I, structural formula II or structural formula II I or their pharmaceutical salts and be used for the treatment of purposes in the diabetes medicament in production;
In another embodiment, the invention further relates to structural formula I, structural formula II or structural formula II I or their pharmaceutical salts and be used for the treatment of purposes in the sexual dysfunction medicine in production;
The compounds of this invention also is effective in treatment and prevent diabetes and male and female sexual dysfunction.And this chemical compound also has the more favourable safety of chemical compound that is used for the treatment of these diseases than current.
Be used to describe term of the present invention and have following meaning.
When the chemical compound of representing with structural formula I, structural formula II or structural formula II I had more than a chirality substituent group, it can exist with the diastereo-isomerism form.Diastereo-isomerism is to can separating by the method (as chromatography or crystallization) known to the those skilled in the art, and the independent enantiomer of each centering can separate with the method that those skilled in the art are familiar with.The present invention includes structural formula I, structural formula II and each diastereomer of structural formula II I chemical compound and their mixture.
Some chemical compound of structural formula I, structural formula II and structural formula II I can exist with the separable different conformation forms of stablizing.Owing to restricted around asymmetric single bonded rotation as because sterically hindered or ring strain produces reverses asymmetric making and can separate different conformers.The present invention includes structural formula I, structural formula II and each conformer of structural formula II I chemical compound and their mixture.
Some chemical compound of structural formula I, structural formula II and structural formula II I can exist with zwitterionic form, and the present invention includes structural formula I, structural formula II or each zwitterionic form of structural formula II I chemical compound and their mixture.
As used herein, " C
1-C
4The straight or branched alkyl " expression has the straight or branched hydrocarbon of 1-4 carbon atom, and this hydrocarbon is complete saturated with unsubstituted." C
3-C
7Cycloalkyl " refer to have saturated, the unsubstituted hydrocarbon ring of 3-7 carbon atom." C
1-C
4The straight or branched alkyl of mixing " refer to have the straight or branched hydrocarbon of 1-4 carbon atom, this hydrocarbon is saturated fully with unsubstituted, it also comprises at least one hetero atom." hetero atom " is nitrogen, oxygen or sulfur." C
3-C
7Heterocyclylalkyl " refer to have saturated, the unsubstituted hydrocarbon ring of 3-7 carbon atom, this ring also comprises at least one " hetero atom ".C
1-C
4Straight or branched alkyl, C
3-C
7Cycloalkyl, C
1-C
4Straight or branched mix alkyl, C
3-C
7Heterocyclylalkyl can be used as similar trim (generic modifier) and is described in a class substituent group on another functional group such as carbonyl, sulfonyl or the sulfonamides." C for example
3-C
7Naphthene base carbonyl " refer to be bonded to saturated, unsubstituted hydrocarbon ring that a class on the carbonyl has 3-7 carbon atom.
" C
8-C
14Bicyclic aryl " refer to have together two or three hydrocarbon rings of condensing of 8-14 carbon atom, as naphthalene.C
8-C
14The dicyclo aromatic ring system has at least one aromatic ring." 5-or 6-unit heteroaryl " refers to have the monocyclic aromatic rings of 5 or 6 atoms, and wherein 1-4 atom is hetero atom." 8-is to 14-unit bicyclic heteroaryl " fourth finger has 8-14 atom, at least one aromatic ring and 1-4 heteroatomic two or three hydrocarbon rings that condense together.
Phenyl, benzyl, benzoyl, C
8-C
14Bicyclic aryl, 5-or 6-unit's heteroaryl or 8-can be unsubstituted or use C to 14-unit bicyclic heteroaryl
1-C
4Straight or branched alkyl, F, Cl, Br ,-OH, methoxyl group, phenyl, benzyl, benzoyl or benzyloxy methyl substituted.And, phenyl, benzyl, benzoyl, C
8-C
14Bicyclic aryl, 5-or 6-unit heteroaryl and 8-can be used as similar trim to 14-unit bicyclic heteroaryl and are described in a class substituent group on another functional group such as carbonyl, sulfonyl or the sulfonamides.For example " C8-C14 bicyclic aryl sulfonyl " refers to be bonded to the dicyclo aromatic ring that a class on the sulfonyl has 8-14 carbon atom.
Modified aminoacid by with aminoacid and on modification place round parentheses to indicate (is that 4-chlorine in the phenylalanine D-isomer is modified as (4-Cl-D-Phe)).As for the part of describing in structural formula I, structural formula II and structural formula II I, one-letter symbol is represented the meaning that had defined and is not referred to corresponding to those alphabetical single-letter aminoacid.
Letter " D " before the above-mentioned 3-letter abbreviations refers to amino acid whose D-form as " D-Phe ".When the single-letter abbreviation is used for aminoacid, " d " will represent amino acid whose D-form (as dF=D-Phe) before letter.
" amino alcohol " is to be the aminoacid that methyl is modified by C-being held carbonyl reduction.Amino alcohol is by general nomenclature " Xaa alcohol " expression, and wherein Xaa is the specific amino acids that carbonyl has been removed from it.In order to illustrate, " Ser alcohol " has corresponding to Ser aminoacid H
2N-CH (CH
2OH)-H of COOH structure
2N-CH (CH
2OH)-CH
2The OH structure.
Refer on ad-hoc location, not comprise amino acid whose structure as " singly-bound " used herein.It is used for representing that aminoacid lacks on that position, to such an extent as to like this from one side having formed peptide bond near the carbonyl of that position with from another side mutually near the amine of that position.
" * " expression D-and L-isomer are all possible.
" Ac " refer to acetyl group (promptly-C (O) CH
3).
" Orn " refers to ornithine.
" hCys " refers to homocysteine.
" hArg " refers to homoarginine.
" Lys (ipr) " refers to lysine (N-isopropyl).
" Cit " refers to citrulline.
" nLeu " leucine of making a comment or criticism.
" Me " fingernail base.
" OME " refers to methoxyl group.
" Cya " refers to cysteic acid.
" Dap " refers to two alanyl.
" Dab " refers to the diamino bytyry.
" MC4 agonist " refers to that the MC4 receptor is had affinity and cause measurable bioactive chemical compound in the cell that contains the MC4 receptor, tissue and organism.It is well known measuring this active detection method.
Term " optionally " expression has the activity of certain receptor of preferential selection rather than other receptor, and this activity can be based on the intact cell, tissue or the living body detection standard measure that show receptor active.Selectivity can be by the EC of the associated receptor that relatively relates to
50And determine.
" officinal salt " refers to the salt to the avirulent substantially structural formula I of mammal, structural formula II or structural formula II I chemical compound.Common officinal salt comprises that those pass through The compounds of this invention and inorganic or organic acid or the salt for preparing with the organic or inorganic alkali reaction.These salt are called as acid-addition salts and base addition salts respectively.Should be realized that it is not critical forming this specific gegenion of inventing the part of arbitrary salt, as long as this salt is pharmaceutically useful generally and as long as gegenion does not provide disadvantageous character to this salt on the whole.
Medicinal " acid-addition salts " is the salt that forms by free alkali form and medicinal acid reaction with formula I chemical compound, as at Encylopedia of Pharmaceutical Technology, editor JamesSwarbrick and James C.Boylan, the 13rd volume (1996) is described in " Preservation ofPharmaceutical Products to Salt Forms of Drugs and Absorption ".The specific salts form includes but not limited to: acetate, benzoate, benzene sulfonate, 4-closilate; Citrate; Esilate; Fumarate; The d-gluconate; The d-glucuronate; Glutarate; Glycollate; Hippurate; Hydrochlorate; The 2-isethionate; The dl-lactate; Maleate; The d-malate; The l-malate; Malonate; The d-mandelate; The l-mandelate; Mesylate; 1, the 5-napadisilate; The 2-naphthalene sulfonate; Phosphate; Salicylate; Succinate; Sulfate; The d-tartrate; L-tartrate and tosilate.
Medicinal " base addition salts " is the salt that forms by free acid form and medicinal basic reaction with formula I chemical compound, as describing among the described Encyclopedia of Pharmaceutical Technology in front.The specific salts form includes but not limited to: and calcium salt, diethanolamine salt, diethyl amine salt, ethylenediamine salt, lysinate, magnesium salt, piperazine salt, potassium salt, sodium salt and front three amine salt (Tris, Trizma).
The chemical compound that term " active component " expression is generally described by the salt of structural formula I, structural formula II or structural formula II I and these chemical compounds.
Term " pharmaceutically acceptable " expression carrier, diluent, excipient and salt must be compatible with other composition of compositions and harmless to their receiver clinically.Pharmaceutical composition of the present invention prepares by methods known in the art with the composition of knowing and obtain easily.
Term " treatment " comprises that meaning that their are usually generally acknowledged promptly alleviates, improves, regulates, stops, suppresses, slows down, slows down, stops or reverses progress or seriousness as pathological conditions described herein or their sequela as used herein.
Disease, discomfort or the morbid state for the treatment of with The compounds of this invention comprise (1) fat (2) diabetes and (3) male and/or female sexual disorder.
" prevent from " to refer to reduce the probability that the receiver could obtain or produce any pathological conditions described herein.Term " prevents from " to be specially adapted to the easy patient who infects as the particular pathologies disease that detects by medical diagnosis.
" pharmacy effective dose " refers to and will cause tissue, system or mammiferous biology or medical response and/or can treat disease described herein or the exciting MC3 of energy and/or the chemical compound of MC4 receptor or the amount of their salt." effective dose " that is administered to experimenter's peptide also will depend on the type and the seriousness of disease or disease and depend on experimenter's characteristic such as holistic health state, age, sex, body weight and to the tolerance of medicine.The doctor who is tried the patient should determine the therapeutic dose used according to correlation circumstance.
Can use pharmacy effective dose to thinking the patient who is easy to take place disease or disease in order to prevent.When in order to prevent to be administered to the patient, the severity of disease that is mediated can be prevented or alleviate to described amount also.The dosage regimen of utilizing The compounds of this invention considers that by the those skilled in the art of medical science or veterinary applications a plurality of factors include but not limited to age of medical history, subject pathology disease or symptom, the seriousness of being controlled disease/symptom and experimenter that route of administration, receiver are previous and sex and select.Yet, should understand the therapeutic dose of using and will consider that correlation circumstance is definite by the doctor in charge.
Usually, the effective minimum daily dose of The compounds of this invention will be above about 0.01mg.Common, effective maximum daily dose will can not surpass about 1000mg.More preferably, effective minimum daily dose will be between 0.05mg and 50mg, more preferably between 0.1mg and 10mg.Most preferably, the effective minimum daily dose of MC4R agonist peptide will and will can not surpass about 20 μ g/kg above about 2 μ g/kg among the present invention.The dosage standard operation standard that may be in accordance with " dose titration (dosetitrating) " receiver in the medicine technology field is determined accurately; Be the initial application low dose compounds, and increase dosage gradually until observing the goal treatment effect.The dosage that separates that target dose can show as single dose or use with appropriate intervals.
" mammal " is animal independently, and described animal is a member of taxonomic Mammalia.Mammalia comprises people, monkey, chimpanzee, gorilla, cattle, pig, horse, sheep, Canis familiaris L., cat, mice and rat.The common doctor in charge can determine to benefit from the people who uses The compounds of this invention and compositions.
Term " patient " comprises people or non-human animal such as companion animals (Canis familiaris L. and cat etc.), domestic animal and laboratory animal.
Term " medicinal " refers to the patient who is tried nontoxic substantially when here as adjective.
The pharmacy effective dose of structural formula I, structural formula II or structural formula II I chemical compound can be used for the preparation to the useful medicine of treatment fat-reducing, obesity, diabetes and male and female sexual dysfunction.
Preparation
Pharmaceutical composition of the present invention prepares by known method with the composition of knowing and obtain easily.This method can comprise mixing as routine, dissolving, granulation, manufacturing sugar-coat, levigate, emulsifying, incapsulates, embedding or step of freeze drying.
Because The compounds of this invention comprises acidic moiety (as carboxyl), The compounds of this invention can be prepared into their medicinal basic addition salts such as sodium salt.Equally, because The compounds of this invention comprises basic moiety (as amino), The compounds of this invention can be prepared as medicinal acid addition salt such as acetate.
In making the present composition, active component (The compounds of this invention) mix with carrier usually or with carrier dilute or the carrier of packing in.When carrier during as diluent, this diluent can be solid, semisolid or the liquid substance as carrier, excipient or the medium of active component.Thereby compositions can be the form as suspension, solution or sterile injectable solution.
Can use suitable dispersant or wetting agent and suspending agent to prepare injectable formulation such as sterile injectable aqueous or oily suspension.Sterile injectable preparation can be at nontoxic parenteral acceptable diluent or solution or the suspension in the solvent, as the solution in 1,3 butylene glycol.Adoptablely accept carrier and solvent is water, sterile water for injection (WFI), bacteriostatic water for injection (BWFI), Ringer's mixture and isotonic sodium chlorrde solution.And the aseptic fixedly oil of conventional employing is as solvent or suspension media.Can adopt fixedly oil ﹠ fat acid to be used for the preparation of injectable formulation as oleic acid.
The compounds of this invention and officinal salt have useful pharmacy characteristic and can be used in the compositions with the The compounds of this invention that contains pharmacy effective dose of one or more pharmaceutically acceptable excipient composition or its officinal salt.Excipient can comprise material such as carrier, diluent, filler, aromatic, sweeting agent, lubricant, solubilizing agent, suspending agent, wetting agent, binding agent, disintegrating agent, capsule material, antibacterial and other conventional adjuvant.The appropriate formulation method depends on the route of administration of selection and any interaction between the excipient.Pharmaceutical composition comprises the active component of about percent 1-99 weight percent usually, and this active component is a The compounds of this invention.
The solid form preparation can comprise powder, tablet and capsule.Solid carrier can be one or more materials that also can be used as aromatic, lubricant, solubilizing agent, suspending agent, bonding agent, tablet disintegrant and capsule material.
Sterile liquid formulations can comprise suspension, Emulsion, syrup, elixir.Can or be suspended in the mixture of pharmaceutically suitable carrier such as sterilized water, aseptic organic solvent or sterilized water and aseptic organic solvent the active component dissolving.For example by filtering, sterilize by radiation or by the form that antibacterial is mixed in aseptic solid composite with the filter that filters antibacterial or virus, wherein said composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before using injectable formulation.
Before being administered to the experimenter who receives treatment, the The compounds of this invention preparation can be become unit dosage forms." unit dosage forms " is the unit that physically separates that contains unit dose, and it is suitable for using in people experimenter or other mammal.For example unit dosage forms can be perhaps many capsules of capsule or tablet or tablet." unit dose " is by calculating the reactive compound of the present invention with the scheduled volume that produces ideal treatment, general and one or more the pharmaceutically acceptable mixed with excipients of wherein said chemical compound.Active principle in the unit dose can change or adjust for about 1000 milligrams from about 0.01-according to the particular treatment that relates to.
The compounds of this invention can be used or can or repeatedly use whole daily doses or use by continous pouring with dosage every day twice, three times of separating with single daily dose.When sending is when being undertaken by endermic form, and it is successive to use that yes.
Can comprise that per os, subcutaneous, local, parenteral (for example intravenous and intramuscular), bronchus or intranasal approach use The compounds of this invention by number of ways.
" continous pouring " of The compounds of this invention refer to the continuity a period of time in controllably parenteral send peptide to the patient.By continous pouring use can by but be not limited to pump, bank, suppository, vaginal suppository, transdermal plaster or use as subcutaneous, intramuscular, endoperitoneal, intravenous, brain in or endarterial other local application (for example buccal administration, sublingual administration, spray, ointment, Emulsion or gel) finish and use.
The pump of sending The compounds of this invention can be implanted in patient's body.Alternatively, the patient can be at the external pump of wearing, and this pump is connected on the patient body by conduit, pin or some other connection means.Can use any pump that is suitable for delivering drugs to the patient.Example comprises as those at U.S. Patent number 6,659, disclosed pump in 982.
Bank is the biocompatible polymeric system that contains The compounds of this invention and send peptide in time.Example comprises microsphere, microcapsule, receive grain, liposome, hydrogel or other polymerization implant.By bank send comprise during agonist preferred a week, two weeks and one month during.If desired, available another bank continues to send peptide and gives the patient.
The transformation The compounds of this invention also will make its half-life with prolongation can continue to send the MC4 receptor stimulating agent to receptor.This modification comprise with bigger albumen such as albumin, antibody and antigen in conjunction with or comprise by being connected fatty acid, Polyethylene Glycol (PEG) polymer and other reagent and increase the chemical modification of half-life.
Depend on desirable targeted therapeutics, The compounds of this invention can use separately effectively or be used in combination with one or more extra activating agents.Therapeutic alliance comprises uses the single medicine dosage composition that contains structural formula I, structural formula II or structural formula II I and one or more extra activating agents, also comprises chemical compound and every kind of activating agent of using structural formula I, structural formula II or structural formula II I with itself independent drug dose dosage form.When using independent dosage particles, can use in the substantially the same time and promptly use or use chemical compound and one or more the extra activating agents of promptly using structural formula I, structural formula II or structural formula II I successively simultaneously with the time of staggering respectively; Conjoint therapy is interpreted as and comprises all these therapeutic schemes.
The preferred conjoint therapy that is used for the treatment of obesity is The compounds of this invention and sibutramine (sibutramine) (or the active metabolite of sibutramine such as demethylated sibutramine and dinor-sibutramine), preferably unites use with an aquation Sibutramine hydrochloride.Another is preferably united is that The compounds of this invention and orlistat (orlistat) are united use.
The preferred conjoint therapy that is used for the treatment of sexual dysfunction (erection problem) is that The compounds of this invention and sildenafil citrate (sildenafil citrate) are united use.Another is preferably united is that The compounds of this invention and Tadalafil (tadalafil) are united use.And another preferably to unite be The compounds of this invention and Vardenafil (vardenafil), preferably unite use with Vardenafil hydrochloric acid.
Embodiment subsequently is not used in and limits the present invention by any way.Be combined to method (Merrifield, J.Am.Chem.Soc.85 volume: 2149-54 page or leaf, 1963) by manual or automatic synthetic technology with solid and can synthesize all peptides of the present invention.With assembling automatically as ABI 431A or 433A synthesizer.
Embodiment 1
No. 48 compd A c-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
According to the diagram A that summarizes below, use the ABI321 instrument by standard Fmoc chemistry assembling Arg-Cys-Glu-His-D-Phe-Arg-Trp-Cys sequence.Single 1.5 hours dicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HOBt) activation methods of the Applied Biosystems, Inc. by using standard are assembled automatically.The solid support that uses is Rink mbha resin (Rink; Tet.Lett.28 volume: 3787-90 page or leaf, 1987) and side chain protected group scheme be: Arg (Pbf), Cys (Trt), Glu (OtBu), Gln (Trt), His (Trt), Trp (Boc), Tyr (tBu).Shielded aminoacid and Rink resin can be available from Nova Biochem company or Midwest Biotech companies.After the chain assembling, finish alpha-amino acetylation with l hour off line under 10 equivalent DIEA among 5 normal acetic anhydrides, dry DMF or the NMP, the room temperature.With the peptide TFA/H that finishes
2O/TIS/EDT (95/2/1/2, v/v) or TFA/H
2The O/TIS/ methyl phenyl ethers anisole (92/2/4/2, v/v) remove that the mixed liquor room temperature was gone protection in following 2 hours simultaneously and cracking from the resin.The vaporising under vacuum solvent washs three times to remove scavenger (scavenger) with the peptide precipitation and with cold diethyl ether then.Crude product is directly used in cyclization.
Cyclization method
By air oxidation in the 0.2M ammonium acetate buffer that is comprising 20% dimethyl sulfoxide (DMSO) in pH 7.0 or by being used in 2 in the 2.7M guanidine buffer that contains 30%DMSO, (2,2 '-pyridyldisulfide) finishes the oxidation of free cysteine sulfydryl to 2 '-pyridyl disulfide.In the ordinary course of things, separate end-product with high performance liquid chromatograph.
Purification
Preparation HPLC technology with standard is finished purification.At once with peptide dilution and go up sample to the HPLC post and with moisture 0.1% trifluoroacetic acid/acetonitrile gradient eluting, the while is monitored under 214nm after the cyclisation.Suitable fragment is collected and lyophilizing.The further sign of end-product is finished with analysis HPLC known in the art and mass spectral analysis, and data are summed up in the following Table 2.
The conversion of acetate
Peptide is adsorbed in uses 0.1%TFA/H
2On O counter-balanced 2.1 * 25cm ZorbaxC18 preparative column.Follow with 2 column volume water washing pillars with 0.1M ammonium acetate/5% acetonitrile of 2 volumes then.With peptide with 2% acetic acid eluting and lyophilizing.
Diagram A:
Following chemical compound is only limited the present invention in order to illustrate and to be not used in as an example by any way.
Embodiment 2
No. 1 compd A c-ring [Cys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and Fmoc-Arg (pbf) respectively in the 6th step and the 8th step.
Embodiment 3
No. 2 compd A c-Cya-Arg-ring [Cys-Ala-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Ala in the 6th step.An extra step of adding promptly adds Fmoc-Cya (Fmoc-cysteic acid) between the 8th step and the 9th step.And the cyclisation of peptide on the resin (formation disulfide bond) is used in 10 equivalent iodine among the DMF and carried out under room temperature 2 hours and implement.
Embodiment 4
No. 3 compd A c-Tyr-Arg-ring [Cys-Ala-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except the 6th step with Fmoc-Ala rather than with Fmoc-Glu (OtBu).Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 5
No. 4 compd A c-Tyr-Arg-ring [Cys-Arg-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except the 6th step with Fmoc-Arg (Pbf) rather than with Fmoc-Glu (OtBu).Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 6
No. 5 compd A c-Tyr-Arg-ring [Cys-Asn-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except the 6th step with Fmoc-Asn rather than with Fmoc-Glu (OtBu).Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 7
No. 6 compd A c-ring [Cys-Asp-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except going on foot without Fmoc-Arg (Pbf) the 8th.Replace Fmoc-Glu (OtBu) in the 6th step with Fmoc-Asp.
Embodiment 8
No. 7 compd A c-Tyr-Arg-ring [Cys-Asp-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Asp in the 6th step.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 9
No. 8 compd A c-ring [Cys-Gln-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except going on foot without Fmoc-Arg (Pbf) the 8th.Replace Fmoc-Glu (OtBu) in the 6th step with Fmoc-Gln.
Embodiment 10
No. 9 compd A c-Tyr-Arg-ring [Cys-Gln-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except: need not the 1st step Fmoc-Cys (Trt); Replace Fmoc-Glu (OtBu) in the 6th step with Fmoc-Gln (Trt).And with going up sample Fmoc-Cys (Trt)-Wang resin (Wang, J.Am.Chem.Soc.95 volume: 1328-33 page or leaf, 1972) replacement Rink resin in advance.
Embodiment 11
No. 10 compd A c-Tyr-Arg-ring [Cys-Gln-His-D-Phe-Arg-Trp-Cys]-OMe
Synthetic:
Can be prepared according to embodiment 10.Behind cracking, cyclisation and the purification peptide (No. 9, chemical compound) is dissolved in the absolute methanol.Then, hydrogen chloride gas is bubbled into about half a minute of methanol solution.Allow reaction at room temperature to carry out ten minutes.Under vacuum, remove and desolvate, and as purification end-product as described in the embodiment 1.
Embodiment 12
No. 11 chemical compound Tyr-Arg-ring [Cys-Gly-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Gly in the 6th step.The 8th step back adds Fmoc-Tyr (tBu).Omit in the 9th step and use the acetic anhydride acetylation.
Embodiment 13
No. 12 compd A c-Tyr-Arg-ring [Cys-Gly-His-D-Phe-Arg-Trp-Cys]-NH
2 Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Gly in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 14
No. 13 compd A c-Tyr-Arg-ring [Cys-His-His-D-Phe-Arg-Trp-Cys]-NH
2 Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-His in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 15
No. 14 compd A c-Tyr-Arg-ring [Cys-Ile-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Ile in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 16
No. 15 compd A c-ring [Cys-Leu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except going on foot without Fmoc-Arg (Pbf) the 8th.Replace Fmoc-Glu (OtBu) in the 6th step with Fmoc-Leu.
Embodiment 17
No. 16 compd A c-ring [Cys-Lys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except going on foot without Fmoc-Arg (Pbf) the 8th.Replace Fmoc-Glu (OtBu) in the 6th step with Fmoc-Lys (Boc).
Embodiment 18
No. 17 compound N-methyl-Tyr-Arg-encircles [Cys-Met-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except going on foot without the acetic anhydride acetylation the 9th.Fmoc-N-methyl-Tyr is used in the 8th step back.And the 6th the step replace Fmoc-Glu (OtBu) with Fmoc-Met.
Embodiment 19
No. 18 compd A c-Tyr-Arg-ring [Cys-Met-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Met in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 20
No. 19 compd A c-Tyr-Arg-ring [Cys-Phe-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Phe in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 21
No. 20 compd A c-Tyr-Arg-ring [Cys-Pro-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Pro in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 22
No. 21 compd A c-Tyr-Arg-ring [Cys-Ser-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Se in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 23
No. 22 compd A c-Tyr-Arg-ring [Cys-Thr-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Thr in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 24
No. 23 compd A c-Tyr-Arg-ring [Cys-Trp-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Trp in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 25
No. 24 compd A c-Tyr-Arg-ring [Cys-Tyr-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Tyr (tBu) in the 6th step.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 26
No. 25 compd A c-Tyr-Arg-ring [Cys-Val-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Val in the 6th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 27
No. 26 compd A c-Arg-ring [Cys-Cya-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Cya in the 6th step.And the 10 normal iodine that are used among the DMF carry out peptide cyclisation in 2 hours (formation disulfide bond) under room temperature on the resin.
Embodiment 28
No. 27 compd A c-D-Arg-ring [Cys-Cya-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step of Fmoc-Cya and Fmoc-D-Arg (pbf) replacement respectively.And the 10 normal iodine that are used among the DMF carry out peptide cyclisation in 2 hours under room temperature on the resin.
Embodiment 29
No. 28 compd A c-Tyr-Arg-ring [Cys-Cya-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Glu (OtBu) with Fmoc-Cya in the 6th step.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).And the 10 normal iodine that are used among the DMF carry out peptide cyclisation in 2 hours under room temperature on the resin.
Embodiment 30
No. 29 chemical compound rings [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except omitting the 8th step and the 9th step.
Embodiment 31
No. 30 compd A c-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except going on foot without Fmoc-Arg (Pbf) the 8th.
Embodiment 32
No. 31 compd A c-ring [Cys-Glu-His-(4-F-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except going on foot without Fmoc-Arg (Pbf) the 8th.And, replace Fmoc-D-Phe in the 4th step with Fmoc-4-F-D-Phe.
Embodiment 33
No. 32 compd A c-ring [Cys-Glu-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-D-Phe with Fmoc-4-Cl-D-Phe in the 4th step.Go on foot without Fmoc-Arg (Pbf) the 8th.
Embodiment 34
No. 33 compd A c-ring [Cys-Glu-His-(4-Br-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except going on foot without Fmoc-Arg (Pbf) the 8th.And, replace Fmoc-D-Phe with Fmoc-4-Br-D-Phe.
Embodiment 35
No. 34 compd A c-ring [Cys-Glu-(the 1-methyl-His)-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-1-methyl-His in the 5th step.Go on foot without Fmoc-Arg (Pbf) the 8th.
Embodiment 36
No. 35 compd A c-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Lys-Pro-NH
2
Synthetic:
Can be prepared according to embodiment 1, except before the 1st step, using Fmoc-Lys (Boc) and Fmoc-Pro.Go on foot without Fmoc-Arg (Pbf) the 8th.
Embodiment 37
No. 36 compd A c-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser-Pro-NH
2Synthetic:
Can be prepared according to embodiment 1, except before the 1st step, using Fmoc-Ser and Fmoc-Pro.Go on foot without Fmoc-Arg (Pbf) the 8th.
Embodiment 38
No. 37 compound N-propiono-rings [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not carrying out for the 8th step.And the 9th step replaced acetic anhydride to carry out with propanoic acid/DCC/HOBt.
Embodiment 39
No. 38 compound N-bytyry-rings [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not carrying out for the 8th step.And the 9th step replaced acetic anhydride to carry out with butanoic acid/DCC/HOBt.
Embodiment 40
No. 39 compound N-valeryl-rings [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not carrying out for the 8th step.And the 9th step replaced acetic anhydride to carry out with valeric acid/DCC/HOBt.
Embodiment 41
No. 40 chemical compound 3-guanidine radicals propiono-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Standard Fmoc chemistry assembling peptide resin Cys (Trt) Glu (OtBu) His (Trt)-D-Phe-Arg (Pbf) Trp (Boc) Cys (Trt)-Rink-PS by former description.Use the obtainable FmocHNCH of the activatory commerce of DCC/HOBt among three times of excessive usefulness DMF then
2CH
2The COOH process resin.30% piperidines that is used among the DMF is removed the Fmoc group, then resin is washed with other DMF and DCM.Then resin is suspended in NMP and with 2.0 normal N among the NMP, N-two (Boc)-1-amidino groups pyrazoles and 2.0 normal DIEA handle and room temperature under jolting spend the night.(Bernatowicz, Wu and Matsueda, J.Org.Chem.57 (8) volume: 2497-2502 page or leaf, 1992).
With NMP, DCM and methanol thorough washing resin.It is negative that the 1,2,3-indantrione monohydrate of unhindered amina subsequently detects.With the resin cracking, go protection, and as described previously with the peptide cyclisation and the purification that obtain.
Embodiment 42
No. 41 chemical compound 4-guanidine radicals bytyry-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2 Synthetic:
As top embodiment 40 preparation peptides, except using FmocHNCH
2CH
2CH
2COOH replaces Fmoc-HNCH
2CH
2COOH.
Embodiment 43
No. 42 chemical compound 5-guanidine radicals valeryl-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
As top embodiment 40 preparation peptides, except using FmocHNCH
2CH
2CH
2CH
2COOH replaces FmocHNCH
2CH
2COOH.
Embodiment 44
No. 43 compd A c-Dap-ring [Cys-Clu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be handled the ArgCysGluHis-D-PheArgTrpCys resin except using without acetic anhydride by DCC/HOBt activatory 3.0 normal N-α-Fmoc-N-β-tBoc-L-diaminopropionic acid.Remove N end Fmoc group by handling with 30% piperidines among the DMF.Handled free N end 1 hour with 5 equivalent acetic anhydrides in the dry DMF and 10 equivalent DIEA under the room temperature.Carry out resin cracking, cyclisation and purification as embodiment 1.
Embodiment 45
No. 44 compd A c-Dab-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be handled the Arg-Cys-Glu-His-D-Phe-Arg-Trp-Cys resin except using without acetic anhydride by DCC/HOBt activatory 3.0 normal N-α-Fmoc-N-γ-tBoc-L-DAB.Remove N end Fmoc group by handling with 30% piperidines among the DMF.Handled free N end 1 hour with 5 equivalent acetic anhydrides in the dry DMF and 10 equivalent DIEA under the room temperature.Carry out resin cracking, cyclisation and purification as embodiment 1.
Embodiment 46
No. 45 compd A rg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except going on foot without the acetic anhydride acetylation the 9th.And, replace the Rink resin with the Wang resin.
Embodiment 47
No. 46 Compound D-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (pbf) with Fmoc-D-Arg (pbf) in the 8th step.And that did not carry out for the 9th step uses the acetic anhydride acetylation.
Embodiment 48
No. 47 compd A c-D-Arg-ring [Cys-Glu-His-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except using Fmoc-D-Phe and the Fmoc-Arg (pbf) in the 8th step in the 4th step of Fmoc-Phe and Fmoc-D-Arg (pbf) replacement respectively.
Embodiment 49
No. 48 compd A c-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1.
Embodiment 50
No. 49 compd A c-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except replacing the Rink resin with the Wang resin.
Embodiment 51
No. 50 compd A c-Arg-ring [Cys-Glu-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-D-Phe with Fmoc-4-Cl-D-Phe in the 4th step.
Embodiment 52
No. 51 compd A c-Arg-ring [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic and Ac-Arg-ring [Cys-Glu-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-(1-Me-His) in the 5th step.Because the not protection side chain of Fmoc-(1-Me-His), this residue racemization and two kinds of peptides are provided in coupling process:
Ac-Arg-encircles [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2With
Ac-Arg-encircles [Cys-Glu-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 53
No. 52 compd A c-D-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-D-Arg (Pbf) in the 8th step.
Embodiment 54
No. 53 compd A c-D-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (pbf) with Fmoc-D-Arg (pbf) in the 8th step.And, replace the Rink resin with the Wang resin.
Embodiment 55
No. 54 compd A c-hArg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-hArg (Pbf) in the 8th step.
Embodiment 56
No. 55 compd A c-Cit-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Cit in the 8th step.
Embodiment 57
No. 56 compd A c-Cit-ring [Cys-Glu-(the 1-methyl-His)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic and Ac-Cit-ring [Cys-Glu-(1-methyl D-His)-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-1-methyl-His in the 5th step.Replace Fmoc-Arg (Pbf) in the 8th step with Fmoc-Cit.Because Fmoc-(the not protection side chain of 1-methyl-His), this residue racemization and two kinds of peptides are provided in coupling process:
The Ac-Cit-ring [Cys-Glu-(the 1-methyl-His)-D-Phe-Arg-Trp-Cys]-NH
2With
The Ac-Cit-ring [Cys-Glu-(the 1-methyl D-His)-D-Phe-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 58
No. 57 compd A c-Leu-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Leu in the 8th step.
Embodiment 59
No. 58 compd A c-Lys-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Lys (Boc) in the 8th step.
Embodiment 60
No. 59 compd A c-Lys (ipr)-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except (Boc) replacing Fmoc-Arg (Pbf) with Fmoc-Lys (ipr) in the 8th step.
Embodiment 61
No. 60 compd A c-nLeu-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-nLeu in the 8th step.
Embodiment 62
No. 61 compd A c-nLeu-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser-Pro-NH
2
Synthetic:
Can be prepared according to embodiment 1, except before the 1st step, using Fmoc-Ser and Fmoc-Pro.And the 8th the step replace Fmoc-Arg (Pbf) with Fmoc-nLeu.
Embodiment 63
No. 62 compd A c-Orn-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Orn in the 8th step.
Embodiment 64
No. 63 compd A c-Val-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Val in the 8th step.
Embodiment 65
No. 64 compound N-(2-naphthalene sulfonyl base)-D-Arg-rings
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be replaced Fmoc-Arg (pbf) and the 9th in the 8th step acetic anhydride in going on foot except using Fmoc-D-Arg (pbf) and 2-naphthalene sulfonyl chloride respectively.
Embodiment 66
No. 65 compound N-(4-(2-naphthalene sulfonamido)-4-oxo-bytyry)-
D-Are-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be replaced Fmoc-Arg (pbf) and the 9th in the 8th step acetic anhydride in going on foot except using Fmoc-D-Arg (pbf) and succinic anhydride respectively.Following the naphthalene 2 '-sulfonamide that connects: after the 9th step, resin expanded in DCM and with dry DMF washing several.DMAP (4-(N, N '-dimethylamino) pyridine) with 5 equivalent naphthalenes, 2 '-sulfonamide, 10 equivalent PyBOP and 10 equivalent DIEA and catalytic amount in the dry DMF adds to resin then.Coupling reaction allows at room temperature to carry out 3 hours, with resin washing and dry.
Embodiment 67
No. 66 chemical compound 3-(4-hydroxyphenyl) propiono-Arg-ring
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be handled the Arg-Cys-Glu-His-D-Phe-Arg-Trp-Cys resin except using without acetic anhydride by the activatory excessive 3-of DCC/HOBt (4-hydroxyphenyl) propanoic acid.Carry out cyclisation and purification as embodiment 1.
Embodiment 68
No. 67 chemical compound 3-(4-methyl benzoyl) propiono-Arg-ring
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be handled the Arg-Cys-Glu-His-D-Phe-Arg-Trp-Cys resin except using without acetic anhydride by the activatory excessive 3-of DCC/HOBt (4-methyl benzoyl) propanoic acid.Carry out cyclisation and purification as embodiment 1.
Embodiment 69
No. 68 chemical compound Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except going on foot without the acetic anhydride acetylation the 9th.The 8th step back adds Fmoc-Tyr (tBu).
Embodiment 70
No. 69 chemical compound Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except going on foot without the acetic anhydride acetylation the 9th.The 8th step back adds Fmoc-Tyr (tBu).And replace the Rink resin with the Wang resin.
Embodiment 71
No. 70 chemical compound Tyr-Arg-rings
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH-(CH
2)
6-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing the Rink resin with 1 trityl resin (Nash, Bycroft and Chan, Tet.Lett.37 (15) volume: 2625-28 page or leaf, 1996).And do not carry out for the 9th step.
Embodiment 72
No. 71 chemical compound Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Glu-NH
2
Synthetic:
Can be prepared according to embodiment 1, except before the 1st step, using Fmoc-Glu.The 8th step back adds Fmoc-Tyr (tBu).Omit in the 9th step and use the acetic anhydride acetylation.
Embodiment 73
No. 72 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except between the 8th step and the 9th step, adding Fmoc-Tyr (tBu).
Embodiment 74
No. 73 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH
Synthetic:
Can be prepared according to embodiment 1, except between the 8th step and the 9th step, adding Fmoc-Tyr (tBu).Replace the Rink resin with the Wang resin.
Embodiment 75
No. 74 compound N-succinyl-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, be carried out for the 9th step except replace acetic anhydride with succinic anhydride.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 76
No. 75 compound N-glutaryl-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, be carried out for the 9th step except replace acetic anhydride with glutaric anhydride.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 77
No. 76 compound N-glutaryl-Tyr-Arg-encircles [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH
Synthetic:
Can be prepared according to embodiment 1, be carried out for the 9th step except replace acetic anhydride with glutaric anhydride.The 8th step and the 9th step add Fmoc-Tyr (tBu).Replace the Rink resin with the Wang resin.
Embodiment 78
No. 77 compound N-glucose acidic group (gluconoyl)-Tyr-Arg-rings
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not carrying out for the 9th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.Peptide is dissolved among the DMF and spends the night with gluconolactone/DMAP reaction.Purification end-product then.
Embodiment 79
Synthesizing of No. 78 compd A c-Tyr-Arg-rings [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-alcohol:
According to disclosed method (Yan and Mayer, J.Org.Chem.68 (3): 1161-62,2003) commercially available Fmoc-Cys (Trt) alcohol is connected on the deutero-Wang resin of commercially available tribromo-acetyl imines (trichloroacetimidate).Then in the mode of routine with peptide elongation to obtain the Tyr-Arg-Cys-Glu-His-D-Phe-Arg-Trp-Cys alcohol sequence of resin-bonded.As above carry out alpha-amino acetylation 1 hour with 5 equivalent acetic anhydrides in the dry DMF and 10 equivalent DIEA under the room temperature.As above embodiment carries out resin cracking, cyclisation and purification.
Embodiment 80
No. 79 compd A c-Tyr-D-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-D-Arg (Pbf) in the 8th step.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 81
No. 80 compd A c-Tyr-Arg-ring [dCys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Cys (Trt) with Fmoc-D-Cys in the 7th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 82
No. 81 compd A c-Tyr-Arg-ring [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic and No. 82 compd A c-Tyr-Arg-rings
[Cys-Glu-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-(1-Me-His) in the 5th step.And, between the 8th step and the 9th step, add Fmoc-Tyr (tBu).Because the not protected side chain of Fmoc-(1-Me-His), this residue racemization and two kinds of peptide: Ac-Tyr-Arg-ring [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH are provided in coupling process
2With Ac-Tyr-Arg-ring [Cys-Glu-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 83
No. 84 compd A c-Tyr-Arg-rings
[Cys-Glu-(1-Me-His)-(4-F-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic and No. 85 compd A c-Tyr-Arg-ring [Cys-Glu-(1-Me-D-His)-(4-F-D-Phe)-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-1-methyl-His in the 5th step.Replace Fmoc-D-Phe in the 4th step with Fmoc-4-F-D-Phe.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).Because the not protected side chain of Fmoc-(1-Me-His), this residue racemization and two kinds of peptides are provided in coupling process:
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-His)-(4-F-D-Phe)-Arg-Trp-Cys]-NH
2With
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-D-His)-(4-F-D-Phe)-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 84
No. 86 compd A c-Tyr-Arg-ring [Cys-Glu-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-D-Phe with Fmoc-4-Cl-D-Phe in the 4th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 85
No. 87 compd A c-Tyr-Arg-ring [Cys-Glu-(1-Me-His)-(4-Cl-D-Phe)-
Arg-Trp-Cys]-NH
2Synthetic and No. 88 compd A c-Tyr-Arg-rings
[Cys-Glu-(1-Me-D-His)-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-D-Phe and replace Fmoc-His (Trt) with Fmoc-(1-Me-His) with Fmoc-4-Cl-D-Phe in the 4th step respectively in the 5th step.And, between the 8th step and the 9th step, add Fmoc-Tyr (tBu).Because Fmoc-(the not protected side chain of 1-methyl-His), this residue racemization and two kinds of peptides are provided in coupling process:
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-His)-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH
2With Ac-Tyr-Arg-ring [Cys-Glu-(1-Me-DHis)-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 86
No. 89 compd A c-Tyr-Arg-ring [Cys-Glu-His-(4-Br-D-Phe)-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-D-Phe with Fmoc-4-Br-D-Phe in the 4th step.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 87
No. 90 compd A c-Tyr-Arg-ring [Cys-Glu-(1-Me-His)-(4-Br-D-Phe)-Arg-
Trp-Cys]-NH
2Synthetic and No. 91 compd A c-Tyr-Arg-rings
[Cys-Glu-(1-Me-D-His)-(4-Br-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-D-Phe and replace Fmoc-His (Trt) with Fmoc-(1-Me-His) with Fmoc-4-Br-D-Phe in the 4th step respectively in the 5th step.And, between the 8th step and the 9th step, add Fmoc-Tyr (tBu).Because the not protected side chain of Fmoc-(1-Me-His), this residue racemization and two kinds of peptides are provided in coupling process:
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-His)-(4-Br-D-Phe)-Arg-Trp-Cys]-NH
2With
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-D-His)-(4-Br-D-Phe)-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 88
No. 92 compd A c-Tyr-Arg-ring [Cys-Glu-His-(4-Me-D-Phe)-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-D-Phe with Fmoc-4-Me-D-Phe in the 4th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 89
No. 93 compd A c-Tyr-Arg-rings
[Cys-Glu-His-(4-OMe-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-D-Phe with Fmoc-4-OME-D-Phe in the 4th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 90
No. 94 compd A c-Tyr-Arg-rings
[Cys-Glu-(1-Me-His)-(4-OMe-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic
With No. 95 compd A c-Tyr-Arg-rings
[Cys-Glu-(1-Me-D-His)-(4-OMe-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-1-Me-His in the 5th step.Replace Fmoc-D-Phe in the 4th step with Fmoc-4-OMe-D-Phe.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).Because the not protected side chain of Fmoc-(1-Me-His), this residue racemization and two kinds of peptides are provided in coupling process:
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-His)-(4-OMe-D-Phe)-Arg-Trp-Cys]-NH
2With
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Me-D-His)-(4-OMe-D-Phe)-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 91
No. 96 compd A c-Tyr-Arg-ring [Cys-Glu-(3-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-3-Me-His in the 5th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 92
No. 99 compd A c-Tyr-Arg-ring [Cys-Glu-(1-Bzl-His)-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic and No. 100 compd A c-Tyr-Arg-rings
[Cys-Glu-(1-Bzl-D-His)-DPhe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-1-Bzl-His in the 5th step.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).Because the not protected side chain of Fmoc-(1-Bzl-His), this residue racemization and two kinds of peptides are provided in coupling process:
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Bzl-His)-D-Phe-Arg-Trp-Cys]-NH
2With
Ac-Tyr-Arg-encircles [Cys-Glu-(1-Bzl-D-His)-D-Phe-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Bzl-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 93
No. 101 compd A c-Tyr-Arg-rings
[Cys-Glu-(1-Bom-His)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-1-Bom-His in the 5th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 94
No. 110 compd A c-Tyr-Arg-ring [Cys-Glu-(β-(2-furyl)-Ala)-
D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-β-(2-furyl)-Ala in the 5th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 95
No. 111 compd A c-Tyr-Arg-ring [Cys-Glu-(β-(thiophene-2-
Base)-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-β-(thiophene-2-yl)-Ala in the 5th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 96
No. 112 compd A c-Tyr-Arg-ring [Cys-Glu-(β-(1,3-thiazoles-4-
Base)-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-β-(1,3-thiazoles-4-yl)-Ala in the 5th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 97
No. 113 compd A c-Tyr-Arg-ring [Cys-Glu-(β-(pyridine-4-
Base)-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-β-(pyridin-4-yl)-Ala in the 5th step.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 98
No. 114 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-glycinols
Synthetic:
Can be prepared according to embodiment 1, except replacing the Rink resin with glycinol 2-chlorine trityl resin (Barlos, Chatzi, Gatos and Stavropoulos, Int.J.Pept.Protein Res.37 (6) volume: 513-20 page or leaf, 1991).
Embodiment 99
No. 115 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-2-(2-amino
Ethyoxyl) alcoholic acid synthetic:
Can be prepared according to embodiment 1, except using 2-(2-amino ethoxy) ethanol 2-chlorine trityl resin (Barlos, Chatzi, Gatos and Stavropoulos, Int.J.Pept.ProteinRes.37 (6) volume: 513-20 page or leaf, 1991) replaces the Rink resin.
Embodiment 100
No. 116 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser alcohol
Synthetic:
Can be prepared according to embodiment 1, except replacing the Rink resin with the Wang resin.Before step 1, the Wang resin is gone up sample in advance with Fmoc-serinol (tBu) according to disclosed method (Yan and Mayer, J.Org.Chem.68 volume: 1161-62 page or leaf, 2003).Between the 8th step and the 9th step, use Tyr (tBu).
Embodiment 101
No. 117 compd A c-Tyr-Arg-rings
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH-(CH
2)
6-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing the Rink resin with 1 trityl resin (Nash, Bycroft and Chan, Tet.Lett.37 (15) volume: 2625-28 page or leaf, 1996).
Embodiment 102
No. 118 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Glu-NH
2
Synthetic:
Can be prepared according to embodiment 1, except before the 1st step, using Fmoc-Glu (OtBu).Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 103
No. 119 compd A c-Tyr-Arg-rings
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser-Pro-NH
2Synthetic:
Can be prepared according to embodiment 1, except before the 1st step, using Fmoc-Ser and Fmoc-Pro.And between the 8th step and the 9th step, use Fmoc-Tyr.
Embodiment 104
No. 120 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Ser-Pro alcohol
Synthetic:
Can be prepared according to embodiment 1, except replacing the Rink resin with the Wang resin.Before step 1, the Wang resin is gone up sample and added Fmoc-Ser (tBu) subsequently with Fmoc-dried meat ammonia alcohol is pre-according to the method for announcing (Yan and Mayer, J.Org.Chem.68 volume: 1161-62 page or leaf, 2003).And between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 105
No. 121 compd A c-Tyr-Arg-rings
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Lys-Pro-NH
2Synthetic:
Can be prepared according to embodiment 1, except before the 1st step, using Fmoc-Lys (Boc) and Fmoc-Pro.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 106
No. 122 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Lys-Pro alcohol
Synthetic:
Can be prepared according to embodiment 1, except replacing the Rink resin with the Wang resin.Before step 1, the Wang resin is gone up sample and added Fmoc-Lys (Boc) subsequently with Fmoc-dried meat ammonia alcohol is pre-according to the method for announcing (Yan and Mayer, J.Org.Chem.68 volume: 1161-62 page or leaf, 2003).And between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 107
No. 123 compd A c-Tyr-Arg-rings
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-Arg-Phe-NH
2Synthetic:
Can be prepared according to embodiment 1, except before the 1st step, using Fmoc-Arg (Pbf) and Fmoc-Phe.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 108
No. 124 compd A c-Tyr-Cit-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Cit in the 8th step.And between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 109
No. 125 compd A c-Tyr-Cit-rings
[Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic and Ac-Tyr-Cit-ring
[Cys-Glu-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-1-Me-His in the 5th step.Replace Fmoc-Arg (Pbf) in the 8th step with Fmoc-Cit.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).Because the not protected side chain of Fmoc-(1-Me-His), this residue racemization and two kinds of peptides are provided in coupling process:
Ac-Tyr-Cit-encircles [Cys-Glu-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2With
Ac-Cit-encircles [Cys-Glu-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2
These two peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 110
No. 126 compd A c-Tyr-hArg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-hArg (Pbf) in the 8th step.Add Fmoc-Tyr (OtBu) between the 8th step and the 9th step.
Embodiment 111
No. 127 compd A c-Tyr-(l-β-hArg)-ring
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-l-β-hArg (Pbf) in the 8th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 112
No. 128 compd A c-Tyr-Lys-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Lys (Boc) in the 8th step.Use Fmoc-Tyr (tBu) between the 8th step and the 9th step.
Embodiment 113
No. 129 compd A c-Tyr-Ser-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Ser in the 8th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 114
No. 130 compd A c-Tyr-val-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Arg (Pbf) with Fmoc-Val in the 8th step.Between the 8th step and the 9th step, use Fmoc-Tyr (tBu).
Embodiment 115
No. 131 compound N-succinyl-Tyr-Arg-rings
[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, be carried out for the 9th step except replace acetic anhydride with succinic anhydride.Add Fmoc-Tyr (tBu) between the 8th step and the 9th step.Replace the Rink resin with the Wang resin.
Embodiment 116
No. 132 chemical compound rings [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and Fmoc-Arg (Pbf) respectively in the 6th step and the 8th step.And not be used in the 9th step and use the acetic anhydride acetylation.At last, in the 7th step, replace cysteine with homocysteine.
Embodiment 117
No. 133 chemical compound rings [hCys-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, be used the acetic anhydride acetylation except not using the 6th Fmoc-Glu (OtBu) that goes on foot, the Fmoc-Arg (pbf) in the 8th step and noting be used in the 9th step.In the 7th step, replace cysteine with homocysteine.Replace the Rink resin with the Wang resin.
Embodiment 118
No. 134 chemical compound rings [hCys-His-(4-F-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be used the acetic anhydride acetylation except not using the 6th Fmoc-Glu (OtBu) that goes on foot, the Fmoc-Arg (pbf) in the 8th step and noting be used in the 9th step.And replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt), and replace Fmoc-D-Phe with Fmoc-(4-F-D-Phe) in the 4th step in the 7th step.
Embodiment 119
No. 135 chemical compound rings [hCys-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be used the acetic anhydride acetylation except not using the 6th Fmoc-Glu (OtBu) that goes on foot, the Fmoc-Arg (pbf) in the 8th step and noting be used in the 9th step.And use Fmoc-hCys (Trt), and replace Fmoc-D-Phe with Fmoc-4-Cl-D-Phe in the 4th step in the 7th step.
Embodiment 120
No. 136 compd A c-ring [hCys-His-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.And use Fmoc-Phe and Fmoc-hCys (Trt) to replace Fmoc-D-Phe and the Fmoc-Cys (Trt) in the 7th step in the 4th step respectively.
Embodiment 121
No. 137 compd A c-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and Fmoc-Arg (Pbf) respectively in the 6th step and the 8th step.And in the 7th step, replace cysteine with homocysteine.
Embodiment 122
No. 138 compd A c-ring [hCys-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except the 7th the step in replace cysteine with homocysteine, and the 8th the step in omit Fmoc-Arg (Pbf).Replace the Rink resin with the Wang resin.
Embodiment 123
No. 139 compd A c-ring [hCys-His-(4-F-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.In addition, replace Fmoc-Cys (Trt) and replace Fmoc-D-Phe with Fmoc-(4-F-D-Phe) with Fmoc-hCys (Trt) in the 7th step respectively in the 4th step.
Embodiment 124
No. 140 compd A c-ring [hCys-His-(4-Cl-D-Phe)-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and Fmoc-Arg (pbf) in the 6th step and the 8th step.And, use Fmoc-hCys (Trt) and Fmoc-4-Cl-D-Phe to replace the 4th to go on foot and Fmoc-Cys (Trt) and Fmoc-D-Phe in the 7th step respectively.
Embodiment 125
No. 141 compound N-cyclopropane carbonyl-rings [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.With the Fmoc-Cys (Trt) in the 7th step of Fmoc-hCys (Trt) replacement.And, in the 9th step, use with DIC (1, the 3-the DIC)/preactivated cyclopropane carboxylic acid acid substitution of HOBt (I-hydroxybenzotriazole) acetic anhydride.
Embodiment 126
No. 142 compound N-Tetramethylene. carbonyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.In the 7th step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).And, in the 9th step, use to replace acetic anhydride with the preactivated Cyclobutylcarboxylic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 127
No. 143 compound N-Pentamethylene. carbonyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.With the Fmoc-Cys (Trt) in the 7th step of Fmoc-hCys (Trt) replacement.And, in the 9th step, use to replace acetic anhydride with the preactivated Cyclopentane carboxylic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 128
No. 144 compound N-cyclohexane extraction carbonyl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.In the 7th step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).And, in the 9th step, use to replace acetic anhydride with the preactivated cyclohexane-carboxylic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 129
No. 145 compound N-caproyl-rings [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.In the 7th step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).And, in the 9th step, use to replace acetic anhydride with the preactivated n-caproic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 130
No. 146 compound N-benzoyl-rings [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.In the 7th step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).And, in the 9th step, use to replace acetic anhydride with the preactivated benzoic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 131
No. 147 chemical compound 4-phenyl bytyry-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.In the 7th step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).And, in the 9th step, use to replace acetic anhydride with the preactivated 4-phenylbutyric acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 132
No. 148 chemical compound 3-guanidine radicals propiono-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.Use Fmoc-Cys (Trt) and the Fmoc-Arg (pbf) in the 8th step in the 7th step of Fmoc-hCys (Trt) and Fmoc-β-Ala (Fmoc-3-alanine) replacement respectively.And the 9th after the step replaces acetylation: Fmoc to go to protect with following processing (guanidine radicalsization); with 10 equivalent N among the NMP (N-Methyl pyrrolidone), night incubation resin under N '-two (tertbutyloxycarbonyl)-1H-pyrazoles-1-carbonamidine (carboxamidine) and the 10 equivalent DIEA room temperatures.
Embodiment 133
No. 149 chemical compound 5-guanidine radicals valeryl-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.Use Fmoc-hCys (Trt) and Fmoc-5-amino-valeric acid to replace Fmoc-Cys (Trt) and the 8th in the 7th step Fmoc-Arg (pbf) in going on foot respectively.And the 9th after the step replaces acetylation: Fmoc to go protection with following processing (guanidine radicalsization), 10 equivalent N among the usefulness NMP (N-Methyl pyrrolidone), night incubation resin under N '-two (tertbutyloxycarbonyl)-1H-pyrazoles-1-carbonamidine and the 10 equivalent DIEA room temperatures.
Embodiment 134
No. 150 compound N-phenyl sulfonyl-rings [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.And in the 7th step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).Replace acetic anhydride in the 9th step with benzene sulfonyl chloride.
Embodiment 135
No. 151 compound N-(2-naphthalene sulfonyl base)-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can prepare according to embodiment 1, except not using Fmoc-Glu (OtBu) in the 6th step and not using Fmoc-Arg (pbf) in the 8th step.And in the 7th step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).Replace acetic anhydride in the 9th step with the 2-naphthalene sulfonyl chloride.
Embodiment 136
No. 152 compound N-(4-phenyl sulfonamido-4-oxo-bytyry)-rings
[hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.In the 7th step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).Replace acetic anhydride in the 9th step with succinic anhydride.And, add additional step in the 9th step back.Following connection benzsulfamide: after the 9th step, resin expanded in DCM and with dry DMF washing several.DMAP (4-(N, N '-dimethylamino) pyridine) with 5 equivalent benzsulfamides in the dry DMF, 10 equivalent PyBOP and 10 equivalent DIEA and catalytic amount adds to resin then.Allow coupling reaction at room temperature to carry out 3 hours, then with resin washing and dry.
Embodiment 137
No. 153 compd A rg-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, do not used Fmoc-Glu (OtBu) respectively and without the acetic anhydride acetylation except going on foot in the 6th step and the 9th.And in the 7th step, replace cysteine with homocysteine.
Embodiment 138
No. 154 Compound D-Arg-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, do not used Fmoc-Glu (OtBu) respectively and without the acetic anhydride acetylation except replacing the Fmoc-Arg (pbf) in the 8th step with Fmoc-D-Arg (pbf) and going on foot in the 6th step and the 9th.At last, in the 7th step, replace cysteine with homocysteine.
Embodiment 139
No. 155 compd A rg-ring [hCys-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, do not used Glu (OtBu) respectively and without the acetic anhydride acetylation except going on foot in the 6th step and the 9th.And, replace the Rink resin with the Wang resin.At last, in the 7th step, replace cysteine with homocysteine.
Embodiment 140
No. 156 compd A rg-ring [hCys-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic
With No. 157 compd A rg-ring [hCys-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-His (Trt) with Fmoc-(1-Me-His) in the 5th step.Replace Fmoc-Cys (Trt) in the 6th step with Fmoc-hCys (Trt).And not be used in the 9th step and use the acetic anhydride acetylation.Because the not protection side chain of Fmoc-(1-Me-His), this residue racemization and two kinds of peptides are provided in coupling process:
Arg-encircles [hCys-(1-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2With
Arg-encircles [hCys-(1-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2
These two kinds of peptide isomers are easy to separate on HPLC.Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 1-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 141
No. 158 compd A c-Arg-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.And in the 7th step, replace cysteine with homocysteine.
Embodiment 142
No. 159 compd A c-Arg-ring [hCys-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.And in the 7th step, replace cysteine with homocysteine.Replace the Rink resin with the Wang resin at last.
Embodiment 143
No. 160 compd A c-nLeu-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.Use Fmoc-hCys (Trt) and Fmoc-nLeu to replace Fmoc-Cys (Trt) and the 8th in the 7th step Fmoc-Arg (pbf) in going on foot respectively.
Embodiment 144
No. 161 compound N-phenyl sulfonyl-Gly-encircles [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2 Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.And, use Fmoc-hCys (Trt) and Fmoc-Gly to replace the 7th to go on foot and Fmoc-Cys (Trt) and Fmoc-Arg (pbf) in the 8th step respectively.Replace acetic anhydride in the 9th step with benzene sulfonyl chloride.
Embodiment 145
No. 16 chemical compound Tyr-Arg-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, do not used Fmoc-Glu (OtBu) respectively and without the acetic anhydride acetylation except going on foot in the 6th step and the 9th.And between the 8th step and the 9th step, add Fmoc-Tyr (tBu).Replace cysteine in the 7th step with homocysteine at last.
Embodiment 146
No. 163 chemical compound Tyr-Arg-ring [hCys-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except the 9th the step without the acetic anhydride acetylation, and the 7th the step replace cysteine with homocysteine.And at the 8th step back adding Fmoc-Tyr (tBu).Replace the Rink resin with the Wang resin at last.
Embodiment 147
No. 164 compd A c-Tyr-Arg-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except in the 7th step, replacing cysteine with homocysteine.Do not use Fmoc-Glu (OtBu) in the 6th step.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 148
No. 165 compd A c-Tyr-Arg-ring [hCys-His-D-Phe-Arg-Trp-Cys]-OH's is synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu).And in the 7th step, replace cysteine with homocysteine.The 8th step back adds Fmoc-Tyr (tBu).At last, replace the Rink resin with the Wang resin.
Embodiment 149
No. 166 compd A c-Tyr-Arg-ring [hCys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except between the 8th step and the 9th step, using Fmoc-Tyr (tBu).In the 7th step, replace cysteine with homocysteine.
Embodiment 150
No. 167 compd A c-ring [hCys-His-(β-cyclohexyl-D-Ala)-Arg-Trp-Cys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.And (β-cyclohexyl-D-Ala) replaces the Fmoc-D-Phe of the Fmoc-Cys (Trt) and the 4th in the 7th step in going on foot to use Fmoc-hCys (Trt) and Fmoc-respectively.
Embodiment 151
No. 168 compd A c-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.And use Fmoc-penicillamine (Trt) and Fmoc-hCys (Trt) to replace the 1st to go on foot and the Fmoc-Cys (Trt) in the 7th step respectively.
Embodiment 152
No. 169 compd A c-ring [hCys-His-(4-Cl-D-Phe)-Arg-Trp-penicillamine]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.Use Fmoc-penicillamine (Trt), Fmoc-hCys (Trt) and Fmoc-4-Cl-D-Phe to replace the Fmoc-Cys (Trt) and the Fmoc-D-Phe in the 4th step in the 1st step and the 7th step respectively.
Embodiment 153
No. 170 compound N-caproyl-rings [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.Use Fmoc-hCys (Trt) and Fmoc-penicillamine (Trt) to replace the 7th to go on foot and the Fmoc-Cys (Trt) in the 1st step respectively.And, in the 9th step, use to replace acetic anhydride with the preactivated n-caproic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 154
No. 171 compound N-Pentamethylene. carbonyl-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.Use Fmoc-penicillamine (Trt) and Fmoc-hCys (Trt) to replace the Fmoc-Cys (Trt) in the 1st step and the 7th step respectively.And, in the 9th step, use to replace acetic anhydride with the preactivated Cyclopentane carboxylic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 155
No. 172 compound N-cyclohexane extraction carbonyl-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.Use Fmoc-hCys (Trt) and Fmoc-penicillamine (Trt) to replace the 7th to go on foot and the Fmoc-Cys (Trt) in the 1st step respectively.And, in the 9th step, use to replace acetic anhydride with the preactivated cyclohexane-carboxylic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 156
No. 173 compound N-benzoyl-rings [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.Use Fmoc-hCys (Trt) and Fmoc-penicillamine (Trt) to replace the 7th to go on foot and the Fmoc-Cys (Trt) in the 1st step respectively.And, in the 9th step, use to replace acetic anhydride with the preactivated benzoic acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 157
No. 174 chemical compound 4-phenyl bytyry-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.Use Fmoc-hCys (Trt) and Fmoc-penicillamine (Trt) to replace the 7th to go on foot and the Fmoc-Cys (Trt) in the 1st step respectively.And, in the 9th step, use to replace acetic anhydride with the preactivated 4-phenylbutyric acid of DIC (1, the 3-DIC)/HOBt (I-hydroxybenzotriazole).
Embodiment 158
No. 175 compound N-(phenyl sulfonyl)-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.And use Fmoc-hCys (Trt) and Fmoc-penicillamine (Trt) to replace the 7th to go on foot and the Fmoc-Cys (Trt) in the 1st step respectively.Replace acetic anhydride in the 9th step with benzene sulfonyl chloride.
Embodiment 159
No. 176 chemical compounds (4-benzsulfamide) bytyry-ring [hCys-His-D-Phe-Arg-Trp-penicillium sp
Amine]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.Replace Fmoc-Arg (pbf) in the 8th step with the Fmoc-γ-An Jidingsuan.And the 7th use Fmoc-hCys (Trt) and Fmoc-penicillamine (Trt) replacement Fmoc-Cys (Trt) respectively in step and the 1st step.Replace acetic anhydride in the 9th step with benzene sulfonyl chloride.
Embodiment 160
No. 177 compd A c-nLeu-ring [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.Use Fmoc-penicillamine (Trt), Fmoc-hCys (Trt) and Fmoc-nLeu to replace the Fmoc-Cys (Trt) and the Fmoc-Arg (pbf) in the 8th step in the 1st step and the 7th step respectively.
Embodiment 161
No. 178 compound N-benzenesulfonyl-Gly-encircles [hCys-His-D-Phe-Arg-Trp-penicillamine]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.And use Fmoc-penicillamine (Trt), Fmoc-hCys (Trt) and Fmoc-Gly to replace the 1st step, the 7th to go on foot and Fmoc-Cys (Trt), Fmoc-Cys (Trt) and Fmoc-Arg (pbf) in the 8th step respectively.Replace acetic anhydride in the 9th step with benzene sulfonyl chloride.
Embodiment 162
No. 179 chemical compound rings [3-sulfo-propiono-His-D-Phe-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be used the acetic anhydride acetylation except not using the 6th Fmoc-Glu (OtBu) that goes on foot, the Fmoc-Arg (pbf) in the 8th step and noting be used in the 9th step.And use Fmoc-hCys (Trt) and (S-Trt)-3-propane thioic acid to replace the Fmoc-Cys (Trt) of the 1st step and the 7th in going on foot respectively.
Embodiment 163
No. 180 chemical compound rings [Cys-His-D-Phe-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and Fmoc-Arg (pbf) in the 6th step and the 8th step.Do not use the acetic anhydride acetylation in the 9th step.And in the 1st step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).
Embodiment 164
No. 181 chemical compound rings [Cys-His-(4-F-D-Phe)-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, be used the acetic anhydride acetylation except not using the 6th Fmoc-Glu (OtBu) that goes on foot, the Fmoc-Arg (pbf) in the 8th step and noting be used in the 9th step.And use Fmoc-hCys (Trt) and Fmoc-(4-F-D-Phe) to replace Fmoc-Cys (Trt) and the 4th in the 1st step Fmoc-D-Phe in going on foot respectively.
Embodiment 165
No. 182 chemical compound rings [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and Fmoc-Arg (pbf) in the 6th step and the 8th step.Not be used in the 9th step and use the acetic anhydride acetylation.And, use Fmoc-hCys (Trt) and Fmoc-4-Cl-D-Phe to replace the 1st to go on foot and Fmoc-Cys (Trt) and Fmoc-D-Phe in the 4th step respectively.
Embodiment 166
No. 183 compd A c-ring [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and Fmoc-Arg (pbf) in the 6th step and the 8th step.And, use Fmoc-hCys (Trt) and Fmoc-4-Cl-D-Phe to replace the 1st to go on foot and Fmoc-Cys (Trt) and Fmoc-D-Phe in the 4th step respectively.
Embodiment 167
No. 184 compd A c-ring [Cys-His-(4-F-D-Phe)-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.And use Fmoc-hCys (Trt) and Fmoc-4-F-D-Phe to replace Fmoc-Cys (Trt) and the 4th in the 1st step Fmoc-D-Phe in going on foot respectively.
Embodiment 168
No. 185 compd A c-ring [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.And use Fmoc-hCys (Trt) and Fmoc-4-Cl-D-Phe to replace Fmoc-Cys (Trt) and the 4th in the 1st step Fmoc-D-Phe in going on foot respectively.
Embodiment 169
No. 186 compd A rg-ring [Cys-His-D-Phe-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except need not the 6th in the step Fmoc-Glu (OtBu) and need not use the acetic anhydride acetylation in the 9th step.And in the 1st step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).
Embodiment 170
No. 187 compd A rg-ring [Cys-His-(4-F-D-Phe)-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except need not the 6th in the step Fmoc-Glu (OtBu) and need not use the acetic anhydride acetylation in the 9th step.And use Fmoc-hCys (Trt) and Fmoc-4-F-D-Phe to replace Fmoc-Cys (Trt) and the 4th in the 1st step Fmoc-D-Phe in going on foot respectively.
Embodiment 171
No. 188 compd A rg-ring [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except need not the 6th in the step Fmoc-Glu (OtBu) and need not use the acetic anhydride acetylation in the 9th step.And, use Fmoc-hCys (Trt) and Fmoc-4-Cl-D-Phe to replace the 1st to go on foot and Fmoc-Cys (Trt) and Fmoc-D-Phe in the 4th step respectively.
Embodiment 172
No. 189 compd A c-Arg-ring [Cys-His-D-Phe-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.And in the 1st step, replace Fmoc-Cys (Trt) with Fmoc-hCys (Trt).
Embodiment 173
No. 190 compd A c-Arg-ring [Cys-His-(4-F-D-Phe)-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.And use Fmoc-hCys (Trt) and Fmoc-4-F-D-Phe to replace Fmoc-Cys (Trt) and the 4th in the 1st step Fmoc-D-Phe in going on foot respectively.
Embodiment 174
No. 191 compd A c-Arg-ring [Cys-His-(4-Cl-D-Phe)-Arg-Trp-hCys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except not using the Fmoc-Glu (OtBu) in the 6th step.And use Fmoc-hCys (Trt) and Fmoc-4-Cl-D-Phe to replace Fmoc-Cys (Trt) and the 4th in the 1st step Fmoc-D-Phe in going on foot respectively.
Embodiment 175
No. 192 compd A c-Tyr-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-hCys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replacing Fmoc-Cys (Trt) with Fmoc-hCys (Trt) in the 1st step.Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 176
No. 193 compd A c-ring [hCys-His-D-Phe-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replace the Fmoc-Cys (Trt) in the 1st step and the 7th step with Fmoc-hCys (Trt).The 6th the step in without Fmoc-Glu (OtBu).The 8th the step in without Fmoc-Arg (Pbf).
Embodiment 177
No. 194 compd A rg-ring [hCys-His-D-Phe-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replace the Fmoc-Cys (Trt) in the 1st step and the 7th step with Fmoc-hCys (Trt).The 6th the step in without Fmoc-Glu (OtBu).Not be used in the 9th step and use the acetic anhydride acetylation.
Embodiment 178
No. 195 compd A c-Arg-ring [hCys-His-D-Phe-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replace the Fmoc-Cys (Trt) in the 1st step and the 7th step with Fmoc-hCys (Trt).Do not use Fmoc-Glu (OtBu) in the 6th step.
Embodiment 179
No. 196 compd A c-Tyr-Arg-ring [hCys-His-D-Phe-Arg-Trp-hCys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except replace the Fmoc-Cys (Trt) in the 1st step and the 7th step with Fmoc-hCys (Trt).The 6th the step in without Fmoc-Glu (OtBu).Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 180
No. 197 compd A c-Tyr-Arg-ring [hCys-Glu-His-D-Phe-Arg-Trp-hCys]-NH
2
Synthetic:
Can be prepared according to embodiment 1, except replace the Fmoc-Cys (Trt) in the 1st step and the 7th step with Fmoc-hCys (Trt).Between the 8th step and the 9th step, add Fmoc-Tyr (tBu).
Embodiment 181
No. 198 compd A c-ring (s-CH2)-S) [Cys-His-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 1, except not using Fmoc-Glu (OtBu) and the Fmoc-Arg (pbf) in the 8th step in the 6th step.And with linear peptides from the resin cracking and go protection after, do not form the cyclisation of disulfide bond.The substitute is, crude product peptide (200mg) is suspended in the 200mL dichloromethane/acetonitrile (1: stirred 30 minutes 1v/v) and under the room temperature that contains 3mL 1.0M TBAF (tetrabutylammonium among the THF).Add 3mL glacial acetic acid cancellation reaction then.Under vacuum, remove and desolvate.
Embodiment 182
No. 83 compd A c-Tyr-Arg-ring [Cys-Glu-His-(4-F-D-Phe)-Arg-Trp-Cys]-NH
2
Synthetic:
Amino acid whose side chain protected scheme is consistent with the tertbutyloxycarbonyl tBoc chemistry of standard, shown in following option b: Cys (4-methyl Bzl), Trp (CHO), 4-F-D-Phe, His (3-bom), Glu (O-cHx), Cys (4-methyl Bzl), Arg (p-Tos), Tyr (2-BrZ).With commercially available mbha resin (Midwest Biotech) as solid support.Be set with the ABI 431A of the standard t-Boc of manufacturer method or the automated process of ABI 433A synthesizer carries out coupling by artificial use with activatory three times of excess of ammonia bases acid each residue of single coupling of DCC/HOBt or by use.Finished the acetylation of N end in following 1 hour with 5 equivalent acetic anhydrides in the dry DMF, 10 equivalent DIEA room temperatures.By the bonded peptide of 20% piperidines process resin that is used among the DMF tryptophan formoxyl is gone protection, use DMF and washed with dichloromethane subsequently.When having metacresol and thiocresol scavenger by handling 1 hour with 0 ℃ of liquid hydrogen fluoride with peptide cracking and go protection from the resin simultaneously.By ether sedimentation, with ether washing, be extracted in the acetic acid aqueous solution and lyophilizing comes recovering peptide.
Cyclization method
By in pH7.0 air oxidation or by being used in 2 in the 2.7M guanidine buffer that contains 30%DMSO, 2 '-pyridyl disulfide is finished the oxidation of free cysteine sulfydryl in the 0.2M ammonium acetate buffer that contains 20% dimethyl sulfoxide (DMSO).Under each situation, separate end-product with high performance liquid chromatography.
Purification
Preparation HPLC technology with standard is finished purification.After the cyclisation at once with peptide dilution and go up sample to the HPLC post and aqueous 0.1% trifluoroacetic acid/acetonitrile gradient eluting monitor at the 214nm place simultaneously.Suitable fragment is collected and lyophilizing.The further sign of end-product is finished with analyzing HPLC and mass spectral analysis.
The conversion of acetate
Peptide is adsorbed in uses 0.1%TFA/H
2On O counter-balanced 2.1 * 25cm Zorbax C18 preparative column.Follow with 2 column volume water washing pillars with 0.1M ammonium acetate/5% acetonitrile of 2 volumes then.With peptide with 2% acetic acid eluting and lyophilizing.
Characterize product and detect HPLC purity with the acceptable method in this area with mass spectrography, the result sums up in the following Table 2.
Option b:
Embodiment 183
No. 97 compd A c-Tyr-Arg-ring [Cys-Glu-(5-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2
Synthetic and No. 98 compd A c-Tyr-Arg-rings
[Cys-Glu-(5-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 182, except replacing Boc-His (3-Bom) with Boc-5-Me-(D/L)-His (3-Boc) in the 5th step.These two kinds of peptide isomers are easy to separate on HPLC, and it provides:
Ac-Tyr-Arg-encircles [Cys-Glu-(5-Me-His)-D-Phe-Arg-Trp-Cys]-NH
2With
Ac-Tyr-Arg-encircles [Cys-Glu-(5-Me-D-His)-D-Phe-Arg-Trp-Cys]-NH
2
Adopt suitable standard peptide and contrast to differentiate the absolute configuration of 5-Me-His residue in every kind of peptide by two dimensional NMR techniques.
Embodiment 184
No. 102 compd A c-Tyr-Arg-ring [Cys-Glu-(1-pyrazolyls-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic and Ac-Tyr-Arg-ring [Cys-Glu-(1-pyrazoles
Base-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic
Can be prepared according to embodiment 182, the Boc-1-pyrazolyl-(D/L) Ala replaces Boc-His (3-Bom) except using in the 5th step.These two kinds of peptide isomers are easy to separate on HPLC, and it provides:
The Ac-Tyr-Arg-ring [Cys-Glu-(the 1-pyrazolyl-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2With
The Ac-Tyr-Arg-ring [Cys-Glu-(the 1-pyrazolyl-Ala)-D-Phe-Arg-Trp-Cys]-NH
2
Adopt suitable standard peptide and contrast to differentiate the absolute configuration of this His residue substitute in every kind of peptide by two dimensional NMR techniques.
Embodiment 185
No. 103 compd A c-Tyr-Arg-ring [Cys-Glu-(4-phenyl-1H-imidazoles-2-base-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic and No. 104 compd A c-Tyr-Arg-rings [Cys-Glu-(4-phenyl-1H-imidazoles-2-base-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 182, Boc-4-phenyl-1H-imidazole radicals-(D/L) Ala replaces Boc-His (3-Bom) except using in the 5th step.These two kinds of peptide isomers are easy to separate on HPLC, and it provides:
The Ac-Tyr-Arg-ring [Cys-Glu-(4-phenyl-1H-imidazoles-2-base-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2
The Ac-Tyr-Arg-ring [Cys-Glu-(4-phenyl-1H-imidazoles-2-base-Ala)-D-Phe-Arg-Trp-Cys]-NH
2
Adopt suitable standard peptide and contrast to differentiate the absolute configuration of this His residue substitute in every kind of peptide by two dimensional NMR techniques.
Embodiment 186
No. 105 compd A c-Tyr-Arg-ring [Cys-Glu-(2-pyrazines-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic and Ac-Tyr-Arg-ring [Cys-Glu-(2-pyrazine
-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic
Can be prepared according to embodiment 182, the Boc-2-pyrazine-(D/L) Ala replaces Boc-His (3-Bom) except using in the 5th step.These two kinds of peptide isomers are easy to separate on HPLC, and it provides:
The Ac-Tyr-Arg-ring [Cys-Glu-(the 2-pyrazine-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2With
The Ac-Tyr-Arg-ring [Cys-Glu-(the 2-pyrazine-Ala)-D-Phe-Arg-Trp-Cys]-NH
2
Adopt suitable standard peptide and contrast to differentiate the absolute configuration of this His residue substitute in every kind of peptide by two dimensional NMR techniques.
Embodiment 187
No. 106 compd A c-Tyr-Arg-ring [Cys-Glu-(β-(and 1,2,4-triazole-3-Base)-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic, No. 107 compd A c-Tyr-Arg-rings [Cys-Glu-(β-(1,2,4-triazole-3-yl)-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic,
No. 108 compd A c-Tyr-Arg-ring [Cys-Glu-(β-((1-benzyl)-1,2,4-triazole-3-Base)-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic and No. 109 compd A c-Tyr-Arg-rings
[Cys-Glu-(β-((1-benzyl)-1,2,4-triazole-3-
Base)-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Synthetic:
Can be prepared according to embodiment 182, except (β-((1-benzyl)-1,2,4-triazole-3-yl)-(D/L) Ala replaces Boc-His (3-Bom) with Boc-in the 5th step.Between the HF burst times, part has been removed the benzyl blocking group, and should syntheticly produce 4 kinds of peptide-isomers.These four kinds of peptide isomers are easy to separate on HPLC, and it provides:
The Ac-Tyr-Arg-ring [Cys-Glu-(β-((1-benzyl)-1,2,4-triazole-3-yl)-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2, Ac-Tyr-Arg-ring [Cys-Glu-(β-(1,2,4-triazole-3-yl)-D-Ala)-D-Phe-Arg-Trp-Cys]-NH
2, Ac-Tyr-Arg-ring [Cys-Glu-(β-((1-benzyl)-1,2,4-triazole-3-yl)-Ala)-D-Phe-Arg-Trp-Cys]-NH
2Encircle with Ac-Tyr-Arg-[Cys-Glu-(β-(1,2,4-triazole-3-yl)-Ala)-D-Phe-Arg-Trp-Cys]-NH
2
Adopt suitable poly saccharide peptide standard product and contrast to differentiate the absolute configuration of this histidine residues substitute in every kind of peptide by two dimensional NMR techniques.
Table 2: analytical data
| Compound number | Theoretical molecular (dalton) | The molecular weight that observes (dalton) | HPLC purity (%) |
| 1 | 890.06 | 889.8 | 91.2 |
| 2 | 1268.47 | 1268.6 | 99.3 |
| 3 | 1280.5 | 1280.16 | 98.4 |
| 4 | 1365.6 | 1364.84 | 99.1 |
| 5 | 1323.5 | 1322.73 | 99.4 |
| 6 | 1005.2 | ||
| 7 | 1324.52 | 1324.07 | 95.8 |
| 8 | 1018.2 | ||
| 9 | 1338.5 | 95.0 | |
| 10 | 1352.6 | 99.0 | |
| 11 | 1224.4 | ＞95 | |
| 12 | 1266.49 | 1266.21 | 98.6 |
| 13 | 1346.58 | 1345.67 | 99.1 |
| 14 | 1322.6 | 1322.53 | 98.8 |
| 15 | 1003.2 | ||
| 16 | 1018.2 | ||
| 17 | 1311.5 | ||
| 18 | 1340.63 | 1340.14 | 97.6 |
| 19 | 1356.62 | 1356.56 | 86.0 |
| 20 | 1306.56 | 1306.28 | 97.5 |
| 21 | 1296.52 | 1296.02 | 98.1 |
| 22 | 1310.55 | 1310.15 | 98.2 |
| 23 | 1395.65 | 1395.02 | 98.0 |
| 24 | 1372.6 | 1372.9 | 94.6 |
| Compound number | Theoretical molecular (dalton) | The molecular weight that observes (dalton) | HPLC purity (%) |
| 25 | 1308.57 | 1308.27 | 98.6 |
| 26 | 1197.39 | ||
| 27 | 1197.39 | ||
| 28 | 1360.56 | 1360.2 | 95.7 |
| 29 | 977.1 | 99.0 | |
| 30 | 1019.2 | ||
| 31 | 1037.2 | ||
| 32 | 1053.6 | ||
| 33 | 1098.1 | ||
| 34 | 1033.21 | 1033.22 | 97.5 |
| 35 | 1244.5 | 1244.4 | 90.3 |
| 36 | 1203.4 | ＞95 | |
| 37 | 1033.2 | ||
| 38 | 1047.2 | ||
| 39 | 1061.2 | ||
| 40 | 1090.26 | 1089.96 | 90.2 |
| 41 | 1104.3 | ||
| 42 | 1132.34 | 1132.47 | 97.3 |
| 43 | 1105.3 | ||
| 44 | 1119.3 | ||
| 45 | 1134.3 | 99.0 | |
| 46 | 1133.32 | 1132.7 | 96.6 |
| 47 | 1175.37 | 1175.2 | 98.6 |
| 48 | 1175.4 | ||
| 49 | 1176.4 | 99.0 |
| Compound number | Theoretical molecular (dalton) | The molecular weight that observes (dalton) | HPLC purity (%) |
| 50 | 1209.8 | ＞95 | |
| 51 | 1189.4 | 1189.56 | 98.7 |
| 52 | 1175.40 | 1175.4 | 98.0 |
| 53 | 1176.35 | ||
| 54 | 1189.4 | ||
| 55 | 1176.3 | ||
| 56 | 1190.38 | 1190.35 | 96.2 |
| 57 | 1132.3 | ||
| 58 | 1147.3 | ||
| 59 | 1189.4 | ||
| 60 | 1132.3 | ||
| 61 | 1316.5 | ＞95 | |
| 62 | 1133.3 | ||
| 63 | 1118.3 | ||
| 64 | 1323.55 | 1323.3 | 94.7 |
| 65 | 1422.64 | 1422.8 | 92.9 |
| 66 | 1281.5 | ||
| 67 | 1307.5 | ||
| 68 | 1296.48 | ||
| 69 | 1297.49 | 1297.29 | 96.1 |
| 70 | 1395.7 | 90.0 | |
| 71 | 1425.62 | 1425.69 | 97.9 |
| 72 | 1338.54 | ||
| 73 | 1339.53 | 1339.34 | 96.7 |
| 74 | 1396.6 |
| Compound number | Theoretical molecular (dalton) | The molecular weight that observes (dalton) | HPLC purity (%) |
| 75 | 1416.6 | ||
| 76 | 1411.59 | 1141.51 | 97.3 |
| 77 | 1474.6 | ||
| 78 | 1325.5 | ＞95.0 | |
| 79 | 1338.55 | 1338.52 | 96.6 |
| 80 | 1338.5 | ||
| 81 | 1352.6 | ＞94.0 | |
| 82 | 1352.6 | 1356.2 | 88.3 |
| 83 | 1356.54 | 1355.95 | 96.0 |
| 84 | 1370.56 | 1370.27 | 96.5 |
| 85 | 1370.56 | 1369.85 | 99.8 |
| 86 | 1372.99 | 1372.19 | 95.5 |
| 87 | 1387.02 | 1387.1 | 95.0 |
| 88 | 1387.02 | 1386.50 | 94.4 |
| 89 | 1417.4 | 92.0 | |
| 90 | 1431.47 | 1431.1 | 97.0 |
| 91 | 1431.47 | 1431.91 | 95.0 |
| 92 | 1352.57 | 1352.16 | 95.8 |
| 93 | 1368.57 | 1368.27 | 96.9 |
| 94 | 1382.6 | 1382.86 | 97.8 |
| 95 | 1382.60 | 1382.40 | 98.6 |
| 96 | 1352.57 | 1352.15 | 96.1 |
| 97 | 1352.57 | 1352.1 | 92.9 |
| 98 | 1352.57 | 1352.2 | 99.2 |
| 99 | 1428.67 | 1428.48 | 97.0 |
| Compound number | Theoretical molecular (dalton) | The molecular weight that observes (dalton) | HPLC purity (%) |
| 100 | 1428.67 | 1428.54 | 96.6 |
| 101 | 1458.7 | 1458.5 | 99.4 |
| 102 | 1338.55 | 1338.2 | 95.0 |
| 103 | 1414.64 | 1414.1 | 95.0 |
| 104 | 1414.64 | 1413.7 | 95.0 |
| 105 | 1350.56 | 1349.8 | 95.0 |
| 106 | 1339.53 | 1338.6 | 97.4 |
| 107 | 1339.53 | 1338.8 | 99.2 |
| 108 | 1429.66 | 1429.1 | 96.7 |
| 109 | 1429.66 | 1429.4 | 89.5 |
| 110 | 1338.54 | 1338.49 | 96.4 |
| 111 | 1354.61 | 1354.10 | 96.5 |
| 112 | 1355.60 | 1355.51 | 94.2 |
| 113 | 1349.57 | 1349.08 | 89.9 |
| 114 | 1382.6 | ＞95 | |
| 115 | 1426.6 | ＞95 | |
| 116 | 1412.6 | ＞95 | |
| 117 | 1437.7 | 90.0 | |
| 118 | 1467.66 | 1467.24 | 97.6 |
| 119 | 1522.4 | ＞95 | |
| 120 | 1509.7 | ＞95 | |
| 121 | 1563.8 | 1563.1 | 99.9 |
| 122 | 1550.8 | ＞95 | |
| 123 | 1641.9 | 1641.8 | 98.1 |
| 124 | 1339.53 | 1339.2 | 94.9 |
| Compound number | Theoretical molecular (dalton) | The molecular weight that observes (dalton) | HPLC purity (%) |
| 125 | 1353.56 | 1353.5 | 94.3 |
| 126 | 1352.57 | 1351.66 | 93.3 |
| 127 | 1352.57 | 1352.58 | 87.0 |
| 128 | 1310.5 | ||
| 129 | 1271.5 | 1271.4 | 98.0 |
| 130 | 1281.5 | ||
| 131 | 1397.57 | 1397.2 | 96.8 |
| 132 | 862.05 | 862.2 | 98.4 |
| 133 | 863.04 | 862.95 | 94.9 |
| 134 | 880.04 | 880.6 | 99.4 |
| 135 | 896.50 | 896.2 | 98.6 |
| 136 | 904.09 | 903.9 | 99.8 |
| 137 | 904.09 | 904.2 | 99.3 |
| 138 | 905.08 | 905.15 | 98.9 |
| 139 | 922.08 | 922.6 | 99.0 |
| 140 | 938.54 | 938.2 | 96.2 |
| 141 | 930.13 | 930.0 | 99.7 |
| 142 | 944.15 | 943.6 | 99.5 |
| 143 | 958.18 | 958.0 | 99.0 |
| 144 | 972.20 | 971.6 | 99.0 |
| 145 | 960.19 | 959.6 | 99.0 |
| 146 | 966.16 | 965.5 | 99.0 |
| 147 | 1008.24 | 1007.8 | 99.0 |
| 148 | 975.17 | 974.6 | 96.5 |
| 149 | 1003.22 | 1002.8 | 99.1 |
| Compound number | Theoretical molecular (dalton) | The molecular weight that observes (dalton) | HPLC purity (%) |
| 150 | 1002.21 | 1002.4 | ＞99 |
| 151 | 1052.27 | 1052.3 | 95.8 |
| 152 | 1101.30 | 1100.8 | 98.8 |
| 153 | 1018.24 | 1018.1 | 97.9 |
| 154 | |||
| 155 | 1019.23 | 1019.01 | 97.0 |
| 156 | 1032.27 | 1032.4 | 79.9 |
| 157 | 1032.27 | 1032.4 | 95.9 |
| 158 | 1060.28 | 1060.31 | 98.4 |
| 159 | 1061.26 | 1061.19 | 97.7 |
| 160 | 1017.25 | 1017.0 | 99.0 |
| 161 | 1059.26 | 1058.6 | 99.5 |
| 162 | 1181.42 | 1181.3 | 97.6 |
| 163 | 1182.4 | 1182.32 | 94.7 |
| 164 | 1223.46 | 1222.89 | 98.1 |
| 165 | 1224.44 | 1224.47 | 98.9 |
| 166 | 1352.6 | ||
| 167 | 910.14 | 910.2 | 97.8 |
| 168 | 932.14 | 931.6 | 97.3 |
| 169 | 966.59 | 966.2 | 93.5 |
| 170 | 988.25 | 987.6 | 99.0 |
| 171 | 986.24 | 986.0 | 99.7 |
| 172 | 1000.26 | 999.6 | 99.0 |
| 173 | 994.21 | 993.6 | 99.8 |
| 174 | 1036.29 | 1035.6 | 99.0 |
| Compound number | Theoretical molecular (dalton) | The molecular weight that observes (dalton) | HPLC purity (%) |
| 175 | 1030.26 | 1029.4 | 99.0 |
| 176 | 1115.37 | 1114.6 | 95.5 |
| 177 | 1045.31 | 1045.2 | 99.8 |
| 178 | 1087.32 | 1086.6 | 97.8 |
| 179 | 847.03 | 846.8 | 97.5 |
| 180 | 862.05 | 862.2 | 93.7 |
| 181 | 880.04 | 879.9 | 99.1 |
| 182 | 896.50 | 896.3 | 96.2 |
| 183 | 904.09 | 904.4 | 98.0 |
| 184 | 922.08 | 922.3 | 98.7 |
| 185 | 938.54 | 938.1 | 98.9 |
| 186 | 1018.24 | 1017.7 | 92.3 |
| 187 | 1036.23 | 1036.4 | 93.9 |
| 188 | 1052.69 | 1052.5 | 98.4 |
| 189 | 1060.28 | 1060.4 | 97.3 |
| 190 | 1078.27 | 1078.6 | 98.3 |
| 191 | 1094.72 | 1094.3 | 99.5 |
| 192 | 1352.6 | 1352.48 | 90.0 |
| 193 | 918.1 | 90.0 | |
| 194 | 1132.3 | 90.0 | |
| 195 | 1074.3 | 1073.7 | 99.0 |
| 196 | 1237.5 | 99.0 | |
| 197 | 1366.6 | 78.0 | |
| 198 | 904.09 | 903.5 | 84.7 |
Embodiment 188
The structure of MC expression of receptor plasmid
The structure of people MC1 expression plasmid: with human gene group DNA (Clontech catalog number (Cat.No.) 6550-1) as template by the PCR MC1cDNA that clones people.In RCR, use and contain the hMC1 gene specific forward primer in start codon (ATG) and EcoRI site and contain termination codon and the hMC1 gene specific reverse primer in XbaI site.To be cloned into by the total length hMC1cDNA that PCR produces in the pUC18/SmaI plasmid (Pharmacia catalog number (Cat.No.) 27-5266-01), and determine correct hMC1 cDNA by dna sequencing.With the pUC18hMC1 of EcoRI and XbaI digestion through order-checking, and subsequently with hMC1 cDNA fragment sub-clone to the pcDNA3.1 (Invitrogen catalog number (Cat.No.) V790-20) to produce expression plasmid pCDNA3-hMC1.
The structure of people MC3 expression plasmid: with human gene group DNA (Clontech catalog number (Cat.No.) 6550-1) as template by the PCR MC3cDNA that clones people.In RCR, use and contain the hMC3 gene specific forward primer in start codon (ATG) and EcoRI site and contain termination codon and the hMC3 gene specific reverse primer in XbaI site.To be cloned into by the total length hMC3cDNA that PCR produces in the pUC18/SmaI plasmid (Pharmacia catalog number (Cat.No.) 27-5266-01), and determine correct hMC3cDNA by dna sequencing.With the pUC18hMC3 of EcoRI and XbaI digestion through order-checking, and subsequently with hMC3cDNA fragment sub-clone to the pcDNA3.1 (Invitrogen catalog number (Cat.No.) V790-20) to produce expression plasmid pCDNA3-hMC3.
The structure of people MC4 expression plasmid: end user's fetal brain cDNA (Clontech catalog number (Cat.No.) 7402-1) as template by PCR with the mode similar MC4 (hMC4) cDNA that clones people to hMC3cDNA.With EcoRI/XbaI digestion hMC4cDNA PCR product, and then with its sub-clone to pCIneo (Promega catalog number (Cat.No.) E1841) and order-checking.The hMC4R plasmid that obtains has two sudden changes, subsequently these two sudden changes is corrected to produce the proteic hMC4 cDNA of the correct hMC4 of coding.The hMC4cDNA sub-clone that to correct then to the pcDNA3.1 to produce expression plasmid pCDNA3-hMC4.
The structure of people MC5 expression plasmid: with human gene group DNA (Clontech catalog number (Cat.No.) 6550-1) as template by the PCR MC5cDNA that clones people.In RCR, use and contain the hMC5 gene specific forward primer in start codon (ATG) and HindIII site and contain termination codon and the hMC5 gene specific reverse primer in XbaI site.To be cloned into by the total length hMC5cDNA that PCR produces in the pUC18/SmaI plasmid (Pharmacia catalog number (Cat.No.) 27-5266-01), and determine correct hMC5cDNA by dna sequencing.With the pUC18hMC5 of EcoRI and XbaI digestion through order-checking, and subsequently with hMC5cDNA fragment sub-clone to the pcDNA3.1 (Invitrogen catalog number (Cat.No.) V790-20) to produce expression plasmid pCDNA3-hMC5.
The stable HEK-293 cell of expressing human MCR: according to Lipofectamine Plus Reagent (Invitrogen catalog number (Cat.No.) 10964-013) method by produce 293 cells of stablizing of expressing whole hMCR with pCDNA3-hMC4R and CRE-luciferase reporter plasmid cotransfection HEK-293 cell.In order to choose stable transfectant, transfection begins after 48 hours the Genticin (G418) of concentration 300 μ g/mL is added in the culture medium.2-3 is after week, and the individual independent clone of 40-50 is selected, breeds and detects luciferase activity with luciferase reporter gene detection kit (Roche, catalog number (Cat.No.) 1814036).About five the stable clones that have by the highly activated luciferase activity of 10nM NDP-α MSH are set up.
Embodiment 189
The full cell cAMP accumulation of melanocortin receptor detects
No phenol red Hank ' s balanced salt solution (HBSS-092), 1M HEPES, Dulbecco ' s improvement Eagle culture medium (DMEM), hyclone (FBS), antibiotic/antifungal solution and sodium acetate are available from GibcoBRL.Triton X-100, ascorbic acid, cAMP and 3-isobutyl group-1-methyl-xanthine (IBMX) is available from Sigma.Bovine serum albumin (BSA) is available from Roche.The anti-sheep pearl of pearl II type of SPA PVT antibodies and
125I cAMP is available from Amersham.Anti-goat cAMP antibody is available from ICN.Based on the no enzyme cell dissociation buffer of Hank ' s available from SpecialtyMedia.NDP-α MSH is available from Calbiochem company.Dimethyl sulfoxine (DMSO) is available from Aldrich company.
Compound
In the agonist detection method, compound is become 10mM and NDP-α MSH (contrast) is prepared into 33.3 μ M liquid storages among the 100%DMSO.With these solution serial dilution in 100%DMSO.With the chemical compound plate further be diluted in the diluted chemical compound buffer (HBSS-092,1mM ascorbic acid, 1mM IBMX, 0.6%DMSO, 0.1%BSA) with produce in the detection method the final concentration scope promptly for chemical compound between 600nM-6pM with for the NDP-α MSH among the 0.5%DMSO to impinging upon between the 100nM-1pM.20 μ L compound solutions are shifted into 4 PET 96 orifice plates (all detections are all carried out twice for each receptor) from this plate.
Cell culture and cytositimulation
HEK 293 cells of personnel selection MC3R or MC4R stable transfection are grown in the DMEM that contains 10%FBS and 1% antibiotic/antifungal solution.Detect the same day, cell is shifted out with no enzyme cell dissociation buffer and in cell buffer (HBSS-092,0.1%BSA, 10mM HEPES) with 1 * 106 cell/mL resuspending.40 μ L cell suspension are added to every hole to be contained in PET 96 orifice plates of chemical compound that 20 μ L diluted or contrast.Plate was hatched under 37 ℃ 20 minutes in water-bath.Stop detecting by adding 50 μ L cancellation buffer (50mM sodium acetate, 0.25%Triton X-100).
The cAMP concentration determination
In SPA buffer (50mM sodium acetate, 0.1%BSA), carry out the radioligand binding assay.Pearl, antibody and radioligand are diluted in the SPA buffer enough volumes are provided for each 96 orifice plate.Add 100 μ L to the detection hole of each cancellation and contain 33.33 μ L pearls, 33.33 μ L antibody and 33.33 μ L
125The mixed liquor of I-cAMP.This is based on the 6.3mg/mL pearl in the final detection volume of 210 μ L, 0.65% anti-goat antibody and 61pM
125I-cAMP (contains 25,000-30, final concentration 000CPM).After hatching in 12 hours plank is counted in Wallac MicroBeta enumerator.
Being used in the standard curve that detects under the similarity condition is the cAMP of pmol with data conversion.Produce agonist with Activity Base software analysis data and render a service (EC50), and the generation relative effectivenes percentage ratio data of comparing with NDP-α MSH.
Table 3:MC4 renders a service and selectivity
| Compound number | MC4K i(nM) | The MC1/MC4 selectivity |
| 1 | 127.80 | 3.91 |
| 2 | 0.39 | 10.70 |
| 3 | 0.41 | 4.00 |
| 4 | 0.23 | 0.26 |
| 5 | 0.42 | 5.00 |
| Compound number | MC4K i(nM) | The MC1/MC4 selectivity |
| 6 | 2.15 | 35.74 |
| 7 | 0.82 | 15.00 |
| 8 | 1.43 | 3.33 |
| 9 | 2.39 | 10.00 |
| 10 | 0.10 | 9.50 |
| 11 | 1.26 | 11.00 |
| 12 | 1.10 | 6.72 |
| 13 | 0.34 | 10.65 |
| 14 | 0.35 | 12.54 |
| 15 | 0.67 | 14.75 |
| 16 | 0.83 | 2.94 |
| 17 | 0.57 | 10.42 |
| 18 | 0.35 | 8.15 |
| 19 | 0.53 | 7.64 |
| 20 | 0.48 | 4.81 |
| 21 | 0.22 | 10.27 |
| 22 | 0.27 | 6.85 |
| 23 | 0.26 | 10.54 |
| 24 | 0.44 | 8.00 |
| 25 | 0.32 | 11.00 |
| 26 | 0.71 | 38.90 |
| 27 | 1.05 | 30.11 |
| 28 | 1.18 | 26.35 |
| 29 | 3.18 | 15.00 |
| 30 | 2.36 | 38.48 |
| 31 | 0.75 | 57.02 |
| 32 | 0.37 | 66.88 |
| 33 | 0.35 | 79.54 |
| 34 | 43.42 | 11.52 |
| 35 | 1.03 | 1.17 |
| 36 | 1.66 | 1.22 |
| 37 | 1.81 | 36.99 |
| 38 | 2.55 | 28.16 |
| Compound number | MC4K i(nM) | The MC1/MC4 selectivity |
| 39 | 2.08 | 19.67 |
| 40 | 0.96 | 25.92 |
| 41 | 0.60 | 58.47 |
| 42 | 0.40 | 44.63 |
| 43 | 1.06 | 11.00 |
| 44 | 0.95 | 15.00 |
| 45 | 3.03 | 30.47 |
| 46 | 0.73 | |
| 47 | 53.32 | |
| 48 | 0.43 | 26.80 |
| 49 | 3.14 | 35.35 |
| 50 | 0.21 | 36.10 |
| 51 | 6.52 | 76.75 |
| 52 | 0.55 | 30.54 |
| 53 | 8.68 | |
| 54 | 0.48 | 20.85 |
| 55 | 1.67 | 28.81 |
| 56 | 23.39 | 21.38 |
| 57 | 2.26 | 29.00 |
| 58 | 0.81 | 31.69 |
| 59 | 0.86 | 20.92 |
| 60 | 1.51 | 29.95 |
| 61 | 0.87 | 1.70 |
| 62 | 0.75 | 46.91 |
| 63 | 2.28 | 30.51 |
| 64 | 0.62 | 4.12 |
| 65 | 6.53 | 2.70 |
| 66 | 0.83 | 13.23 |
| 67 | 0.26 | 9.15 |
| 68 | 0.63 | 14.08 |
| 69 | 3.00 | 18.38 |
| 70 | 0.30 | 2.00 |
| 71 | 2.11 | 5.13 |
| Compound number | MC4K i(nM) | The MC1/MC4 selectivity |
| 72 | 0.78 | 22.31 |
| 73 | 8.78 | 12.77 |
| 74 | 1.21 | 12.00 |
| 75 | 2.31 | 6.00 |
| 76 | 24.23 | 6.00 |
| 77 | 0.41 | 28.38 |
| 78 | 7.28 | 9.00 |
| 79 | 0.57 | 21.79 |
| 80 | 5.27 | 8.24 |
| 81 | 5.93 | 101.69 |
| 82 | 300.86 | 1.66 |
| 83 | 0.26 | 45.95 |
| 84 | 3.32 | 150.60 |
| 85 | 188.06 | 2.66 |
| 86 | 0.13 | 66.21 |
| 87 | 1.11 | 316.25 |
| 88 | 55.14 | 9.07 |
| 89 | 0.11 | 71.43 |
| 90 | 0.86 | 237.22 |
| 91 | 23.65 | 21.14 |
| 92 | 0.52 | 12.06 |
| 93 | 0.65 | 1.48 |
| 94 | 5.12 | 16.97 |
| 95 | 155.83 | 3.21 |
| 96 | 4.01 | 20.87 |
| 97 | 0.58 | 8.03 |
| 98 | 11.54 | 7.43 |
| 99 | 5.66 | 88.42 |
| 100 | 300.24 | 1.67 |
| 101 | 14.00 | 0.97 |
| 102 | 105.01 | 4.76 |
| 103 | 6.62 | 75.59 |
| 104 | 135.91 | 3.68 |
| Compound number | MC4K i(nM) | The MC1/MC4 selectivity |
| 105 | 20.80 | 24.04 |
| 106 | 20.88 | 23.95 |
| 107 | 500.00 | 1.00 |
| 108 | 31.36 | 5.99 |
| 109 | 82.70 | 6.05 |
| 110 | 117.22 | 4.27 |
| 111 | 65.19 | 7.67 |
| 112 | 88.97 | 5.62 |
| 113 | 37.01 | 13.51 |
| 114 | 1.35 | 4.00 |
| 115 | 1.15 | 2.00 |
| 116 | 2.00 | 4.00 |
| 117 | 0.63 | 1.00 |
| 118 | 4.59 | 4.52 |
| 119 | 0.57 | 0.86 |
| 120 | 0.40 | 1.00 |
| 121 | 0.34 | 0.74 |
| 122 | 0.30 | 0.90 |
| 123 | 1.13 | 2.42 |
| 124 | 2.36 | 18.11 |
| 125 | 19.94 | 25.08 |
| 126 | 0.74 | 22.64 |
| 127 | 0.28 | 20.25 |
| 128 | 0.89 | 22.46 |
| 129 | 2.18 | 22.16 |
| 130 | 1.98 | 26.88 |
| 131 | 11.18 | 7.00 |
| 132 | 0.34 | 77.32 |
| 133 | 9.08 | 31.29 |
| 134 | 0.13 | 68.42 |
| 135 | 0.06 | 120.27 |
| 136 | 55.30 | 7.01 |
| 137 | 0.32 | 54.60 |
| Compound number | MC4K i(nM) | The MC1/MC4 selectivity |
| 138 | 3.08 | 38.81 |
| 139 | 0.38 | 44.29 |
| 140 | 0.20 | 128.15 |
| 141 | 0.19 | 83.00 |
| 142 | 0.11 | 35.55 |
| 143 | 0.08 | 19.27 |
| 144 | 0.30 | 14.85 |
| 145 | 0.73 | 3.82 |
| 146 | 0.32 | 27.43 |
| 147 | 0.07 | 0.86 |
| 148 | 0.10 | 51.98 |
| 149 | 0.07 | 51.85 |
| 150 | 2.35 | 12.88 |
| 151 | 4.35 | 14.00 |
| 152 | 1.77 | 7.73 |
| 153 | 0.10 | 41.81 |
| 154 | 0.21 | 36.00 |
| 155 | 0.68 | 55.84 |
| 156 | 1.31 | 158.41 |
| 157 | 28.42 | 17.60 |
| 158 | 0.08 | 50.25 |
| 159 | 0.74 | 49.41 |
| 160 | 0.05 | 0.90 |
| 161 | 0.08 | 2.18 |
| 162 | 0.08 | 30.07 |
| 163 | 2.28 | 19.46 |
| 164 | 0.38 | 7.79 |
| 165 | 1.45 | 13.53 |
| 166 | 25.05 | 9.38 |
| 167 | 93.07 | 3.36 |
| 168 | 1.35 | 212.71 |
| 169 | 0.03 | 1804.00 |
| 170 | 0.13 | 9.00 |
| Compound number | MC4K i(nM) | The MC1/MC4 selectivity |
| 171 | 0.10 | 75.11 |
| 172 | 0.15 | 26.45 |
| 173 | 0.37 | 29.10 |
| 174 | 0.23 | 4.98 |
| 175 | 1.29 | |
| 176 | 0.49 | |
| 177 | 0.05 | |
| 178 | 0.38 | |
| 179 | 93.46 | 5.35 |
| 180 | 16.46 | 30.38 |
| 181 | 6.07 | 45.25 |
| 182 | 0.89 | 185.74 |
| 183 | 9.37 | 53.39 |
| 184 | 2.51 | 97.44 |
| 185 | 0.47 | 269.59 |
| 186 | 5.21 | 11.44 |
| 187 | 2.02 | 20.76 |
| 188 | 0.92 | 29.56 |
| 189 | 2.72 | 23.31 |
| 190 | 0.17 | 367.10 |
| 191 | 0.26 | 127.33 |
| 192 | 36.70 | 1.00 |
| 193 | 2.59 | 26.59 |
| 194 | 2.93 | 10.61 |
| 195 | 0.87 | 32.56 |
| 196 | 2.10 | 4.98 |
| 197 | 21.81 | 1.00 |
| 198 | 16.72 | 13.07 |
Sequence table
＜110〉Eli Lilly Company
＜120〉melanocortin receptor 4 (MC4) agonist and uses thereof
<130>X15871M
<140>PCT/US2004/016625
<141>2004-06-17
<150>US 60/479,740
<151>2003-06-19
<150>US 60/557,347
<151>2004-03-29
<150>US 60/570,676
<151>2004-05-13
<150>US 60/570,737
<151>2004-05-13
<160>201
＜170〉PatentIn version 3 .3
<210>1
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>1
Cys His Phe Arg Trp Cys
1 5
<210>2
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=cysteic acid
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>2
Xaa Arg Cys Ala His Phe Arg Trp Cys
1 5
<210>3
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜222〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>3
Tyr Arg Cys Ala His Phe Arg Trp Cys
1 5
<210>4
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>4
Tyr Arg Cys Arg His Phe Arg Trp Cys
1 5
<210>5
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>5
Tyr Arg Cys Asn His Phe Arg Trp Cys
1 5
<210>6
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>6
Cys Asp His Phe Arg Trp Cys
1 5
<210>7
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>7
Tyr Arg Cys Asp His Phe Arg Trp Cys
1 5
<210>8
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>8
Cys Gln His Phe Arg Trp Cys
1 5
<210>9
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<400>9
Tyr Arg Cys Gln His Phe Arg Trp Cys
1 5
<210>10
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉replace OH with methoxyl group
<400>10
Tyr Arg Cys Gln His Phe Arg Trp Cys
1 5
<210>11
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>11
Tyr Arg Cys Gly His Phe Arg Trp Cys
1 5
<210>12
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>12
Tyr Arg Cys Gly His Phe Arg Trp Cys
1 5
<210>13
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<40O>13
Tyr Arg Cys His His Phe Arg Trp Cys
1 5
<210>14
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>14
Tyr Arg Cys Ile His Phe Arg Trp Cys
1 5
<210>15
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>15
Cys Leu His Phe Arg Trp Cys
1 5
<210>16
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>16
Cys Lys His Phe Arg Trp Cys
1 5
<210>17
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉methylate
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>17
Tyr Arg Cys Met His Phe Arg Trp Cys
1 5
<210>18
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>18
Tyr Arg Cys Met His Phe Arg Trp Cys
1 5
<210>19
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>19
Tyr Arg Cys Phe His Phe Arg Trp Cys
1 5
<210>20
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>20
Tyr Arg Cys Pro His Phe Arg Trp Cys
1 5
<210>21
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>21
Tyr Arg Cys Ser His Phe Arg Trp Cys
1 5
<210>22
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>22
Tyr Arg Cys Thr His Phe Arg Trp Cys
1 5
<210>23
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>23
Tyr Arg Cys Trp His Phe Arg Trp Cys
1 5
<210>24
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>24
Tyr Arg Cys Tyr His Phe Arg Trp Cys
1 5
<210>25
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>25
Tyr Arg Cys Val His Phe Arg Trp Cys
1 5
<210>26
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=cysteic acid
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉amidatioon
<400>26
Arg Cys Xaa His Phe Arg Trp Cys
1 5
<210>27
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉D type
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=cysteic acid
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>27
Arg Cys Xaa His Phe Arg Trp Cys
1 5
<210>28
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MISC_FEATURE
<222>(4)..(4)
＜223〉Xaa=cysteic acid
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>28
Tyr Arg Cys Xaa His Phe Arg Trp Cys
1 5
<210>29
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>29
Cys Glu His Phe Arg Trp Cys
1 5
<210>30
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>30
Cys Glu His Phe Arg Trp Cys
1 5
<210>31
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>31
Cys Glu His Phe Arg Trp Cys
1 5
<210>32
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>32
Cys Glu His Phe Arg Trp Cys
1 5
<210>33
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉the 4-bromine replaces, the D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>33
Cys Glu His Phe Arg Trp Cys
1 5
<210>34
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>34
Cys Glu His Phe Arg Trp Cys
1 5
<210>35
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>35
Cys Glu His Phe Arg Trp Cys Lys Pro
1 5
<210>36
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>36
Cys Glu His Phe Arg Trp Cys Ser Pro
1 5
<210>37
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-propiono replaces
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>37
Cys Glu His Phe Arg Trp Cys
1 5
<210>38
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-bytyry replaces
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>38
Cys Glu His Phe Arg Trp Cys
1 5
<210>39
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-valeryl replaces
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>39
Cys Glu His Phe Arg Trp Cys
1 5
<210>40
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉3-guanidine radicals propiono replaces
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>40
Cys Glu His Phe Arg Trp Cys
1 5
<210>41
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉4-guanidine radicals bytyry replaces
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>41
Cys Glu His Phe Arg Trp Cys
1 5
<210>42
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉5-guanidine radicals valeryl replaces
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>42
Cys Glu His Phe Arg Trp Cys
1 5
<210>43
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetyl group diaminourea propiono replaces
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>43
Cys Glu His Phe Arg Trp Cys
1 5
<210>44
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetyl group diaminourea bytyry replaces
<220>
＜221〉disulphide
<222>(1)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>44
Cys Glu His Phe Arg Trp Cys
1 5
<210>45
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<400>45
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>46
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉D type
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>46
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>47
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉D type
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>47
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>48
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>48
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>49
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<400>49
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>50
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>50
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>51
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>51
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>52
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉D type
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>52
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>53
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉D type
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<400>53
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>54
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homoarginine
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>54
Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>55
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=citrulline
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>55
Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>56
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=citrulline
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>56
Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>57
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>57
Leu Cys Glu His Phe Arg Trp Cys
1 5
<210>58
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>58
Lys Cys Glu His Phe Arg Trp Cys
1 5
<210>59
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=N (ε)-isopropyl lysine
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>59
Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>60
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=nor-leucine
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>60
Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>61
<211>10
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=nor-leucine
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(10)..(10)
＜223〉amidatioon
<400>61
Xaa Cys Glu His Phe Arg Trp Cys Ser Pro
1 5 10
<210>62
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=ornithine
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>62
Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>63
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>63
Val Cys Glu His Phe Arg Trp Cys
1 5
<210>64
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-(2-naphthalene sulfonyl base) replaces, the D type
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>64
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>65
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-(2-naphthalene sulfonyl base amino-4-oxo-bytyry) replaces, D
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>65
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>66
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉3-(4-hydroxyphenyl) propiono replaces
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>66
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>67
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉3-(4-methyl benzoyl) propiono replaces
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>67
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>68
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>68
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>69
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<400>69
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>70
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉NH-(CH2) 6-NH2 replaces
<400>70
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>71
<211>10
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(10)..(10)
＜223〉amidatioon
<400>71
Tyr Arg Cys Glu His Phe Arg Trp Cys Glu
1 5 10
<210>72
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>72
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>73
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<400>73
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>74
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-succinyl replaces
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>74
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>75
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-glutaryl replaces
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<100>75
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>76
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-glutaryl replaces
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<400>76
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>77
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the glucose acidic group replaces
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>77
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>78
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉be reduced to amino alcohol from aminoacid
<400>78
Tyr Arg Cys Glu His Phe Arg Trp Xaa
1 5
<210>79
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MOD_RES
<222>(2)..(2)
＜223〉D type
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>79
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>80
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>80
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>81
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>81
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>82
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>82
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>83
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>83
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>84
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>84
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>85
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>85
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>86
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>86
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>87
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>87
Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>88
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>88
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>89
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-bromine replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>89
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>90
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-bromine replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>90
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>91
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-bromine replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>91
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>92
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉4-is methyl substituted, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>92
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>93
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-methoxyl group replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>93
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>94
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-methoxyl group replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>94
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>95
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉the 4-methoxyl group replaces, the D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>95
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>96
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉3-is methyl substituted
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>96
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>97
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉5-is methyl substituted
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>97
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>98
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉5-is methyl substituted, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>98
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>99
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉the 1-benzyl replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>99
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>100
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉the 1-benzyl replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>100
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>101
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉the 1-benzyloxymethyl replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>101
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>102
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉the 1-pyrazoles replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>102
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>103
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉4-phenyl-1H-imidazoles-2-base replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>103
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>104
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉4-phenyl-1H-imidazoles-2-base replaces the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>104
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>105
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉the 2-pyrazine replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>105
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>106
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉β-(1,2,4-triazole-3-yl) replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>106
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>107
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉β-(1,2,4-triazole-3-yl) replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>107
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>108
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉β-((1-benzyl) 1,2,4-triazole-3-yl) replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>108
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>109
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉β-((1-benzyl) 1,2,4-triazole-3-yl) replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>109
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>110
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉β-(2-furyl) replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>110
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>111
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉β-(thiophene-2-yl) replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>111
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>112
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉β-(1,3-thiazoles-4-yl) replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>112
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>113
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222><5)..(5)
＜223〉β-(pyridin-4-yl) replaces
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>113
Tyr Arg Cys Glu Ala Phe Arg Trp Cys
1 5
<210>114
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉glycinol replaces
<400>114
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>115
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉2-(2-amino ethoxy) ethanol replaces
<400>115
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>116
<211>10
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(10)..(10)
＜223〉be reduced to amino alcohol from aminoacid
<400>116
Tyr Arg Cys Glu His Phe Arg Trp Cys Xaa
1 5 10
<210>117
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉NH-(CH2) 6-NH2 replaces
<400>117
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>118
<211>10
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(10)..(10)
＜223〉amidatioon
<400>118
Tyr Arg Cys Glu His Phe Arg Trp Cys Glu
1 5 10
<210>119
<211>11
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(11)..(11)
＜223〉amidatioon
<400>119
Tyr Arg Cys Glu His Phe Arg Trp Cys Ser Pro
1 5 10
<210>120
<211>11
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(11)..(11)
＜223〉be reduced to amino alcohol from aminoacid
<400>120
Tyr Arg Cys Glu His Phe Arg Trp Cys Ser Xaa
1 5 10
<210>121
<211>11
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(11)..(11)
＜223〉amidatioon
<400>121
Tyr Arg Cys Glu His Phe Arg Trp Cys Lys Pro
1 5 10
<210>122
<211>11
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(11)..(11)
＜223〉be reduced to amino alcohol from aminoacid
<400>122
Tyr Arg Cys Glu His Phe Arg Trp Cys Lys Xaa
1 5 10
<210>123
<211>11
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(11)..(11)
＜223〉amidatioon
<400>123
Tyr Arg Cys Glu His Phe Arg Trp Cys Arg Phe
1 5 10
<210>124
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=citrulline
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>124
Tyr Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>125
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=citrulline
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>125
Tyr Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>126
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homoarginine
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>126
Tyr Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>127
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=1-β-homoarginine
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>127
Tyr Xaa Cys Glu His Phe Arg Trp Cys
1 5
<210>128
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>128
Tyr Lys Cys Glu His Phe Arg Trp Cys
1 5
<210>129
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>129
Tyr Ser Cys Glu His Phe Arg Trp Cys
1 5
<210>130
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<400>130
Tyr Val Cys G1u His Phe Arg Trp Cys
1 5
<210>131
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-succinyl replaces
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<400>131
Tyr Arg Cys Glu His Phe Arg Trp Cys
1 5
<210>132
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>132
Xaa His Phe Arg Trp Cys
1 5
<210>133
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<400>133
Xaa His Phe Arg Trp Cys
1 5
<210>134
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>134
Xaa His Phe Arg Trp Cys
1 5
<210>135
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>135
Xaa His Phe Arg Trp Cys
1 5
<210>136
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>136
Xaa His Phe Arg Trp Cys
1 5
<210>137
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉second Guangization
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>137
Xaa His Phe Arg Trp Cys
1 5
<210>138
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<400>138
Xaa His Phe Arg Trp Cys
1 5
<210>139
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>139
Xaa His Phe Arg Trp Cys
1 5
<210>140
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>140
Xaa His Phe Arg Trp Cys
1 5
<210>141
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-cyclopropane carbonyl replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>141
Xaa His Phe Arg Trp Cys
1 5
<210>142
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-Tetramethylene. carbonyl substituted
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>142
Xaa His Phe Arg Trp Cys
1 5
<210>143
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-Pentamethylene. carbonyl substituted
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>143
Xaa His Phe Arg Trp Cys
1 5
<210>144
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-cyclohexane extraction carbonyl substituted
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>144
Xaa His Phe Arg Trp Cys
1 5
<210>145
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-caproyl replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>145
Xaa His Phe Arg Trp Cys
1 5
<210>146
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-benzoyl replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>146
Xaa His Phe Arg Trp Cys
1 5
<210>147
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉4-phenyl bytyry replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>147
Xaa His Phe Arg Trp Cys
1 5
<210>148
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉3-guanidine radicals propiono replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>148
Xaa His Phe Arg Trp Cys
1 5
<210>149
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉5-guanidine radicals valeryl replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>149
Xaa His Phe Arg Trp Cys
1 5
<210>150
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-phenyl sulfonyl replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>150
Xaa His Phe Arg Trp Cys
1 5
<210>151
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-(2-naphthalene sulfonyl base) replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>151
Xaa His Phe Arg Trp Cys
1 5
<210>152
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-(4-phenyl sulfonamido-4-oxo-bytyry) replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>152
Xaa His Phe Arg Trp Cys
1 5
<210>153
<211>7
<212>PRT
＜213〉artificial
<220>
＜222〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>153
Arg Xaa His Phe Arg Trp Cys
1 5
<210>154
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉D type
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>154
Arg Xaa His Phe Arg Trp Cys
1 5
<210>155
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<400>155
Arg Xaa His Phe Arg Trp Cys
1 5
<210>156
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉1-is methyl substituted
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>156
Arg Xaa His Phe Arg Trp Cys
1 5
<210>157
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉1-is methyl substituted, the D type
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>157
Arg Xaa His Phe Arg Trp Cys
1 5
<210>158
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>158
Arg Xaa His Phe Arg Trp Cys
1 5
<210>159
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>159
Arg Xaa His Phe Arg Trp Cys
1 5
<210>160
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=nor-leucine
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>160
Xaa Xaa His Phe Arg Trp Cys
1 5
<210>161
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉phenyl sulfonyl replaces
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<400>161
Gly Xaa His Phe Arg Trp Cys
1 5
<210>162
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(3)..(8)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>162
Tyr Arg Xaa His Phe Arg Trp Cys
1 5
<210>163
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(3)..(8)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<400>163
Tyr Arg Xaa His Phe Arg Trp Cys
1 5
<210>164
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(8)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>164
Tyr Arg Xaa His Phe Arg Trp Cys
1 5
<210>165
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(8)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<400>165
Tyr Arg Xaa His Phe Arg Trp Cys
1 5
<210>166
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(8)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<400>166
Tyr Arg Xaa Glu His Phe Arg Trp Cys
1 5
<210>167
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉β-cyclohexyl replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>167
Xaa His Ala Arg Trp Cys
1 5
<210>168
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>168
Xaa His Phe Arg Trp Xaa
1 5
<210>169
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>169
Xaa His Phe Arg Trp Xaa
1 5
<210>170
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-caproyl replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>170
Xaa His Phe Arg Trp Xaa
1 5
<210>171
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-Pentamethylene. carbonyl substituted
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>171
Xaa His Phe Arg Trp Xaa
1 5
<210>172
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉N-cyclohexane extraction carbonyl substituted
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>172
Xaa His Phe Arg Trp Xaa
1 5
<210>173
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-benzoyl replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>173
Xaa His Phe Arg Trp Xaa
1 5
<210>174
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉4-phenyl bytyry replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>174
Xaa His Phe Arg Trp Xaa
1 5
<210>175
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-phenyl sulfonyl replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>175
Xaa His Phe Arg Trp Xaa
1 5
<210>176
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉(4-benzsulfamide) bytyry replaces
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=penicillamine
<400>176
Xaa His Phe Arg Trp Xaa
1 5
<210>177
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=nor-leucine
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=penicillamine
<400>177
Xaa Xaa His Phe Arg Trp Xaa
1 5
<210>178
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉the N-phenyl sulfonyl replaces
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=penicillamine
<400>178
Gly Xaa His Phe Arg Trp Xaa
1 5
<210>179
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=deaminizating Cys
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=homocysteine
<400>179
Xaa His Phe Arg Trp Xaa
1 5
<210>180
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=homocysteine
<400>180
Cys His Phe Arg Trp Xaa
1 5
<21O>181
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=homocysteine
<400>181
Cys His Phe Arg Trp Xaa
1 5
<210>182
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=homocysteine
<400>182
Cys His Phe Arg Trp Xaa
1 5
<210>183
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=homocysteine
<400>183
Cys His Phe Arg Trp Xaa
1 5
<210>184
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=homocysteine
<400>184
Cys His Phe Arg Trp Xaa
1 5
<210>185
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=homocysteine
<400>185
Cys His Phe Arg Trp Xaa
1 5
<210>186
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=homocysteine
<400>186
Arg Cys His Phe Arg Trp Xaa
1 5
<210>187
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=homocysteine
<400>187
Arg Cys His Phe Arg Trp Xaa
1 5
<210>188
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=homocysteine
<400>188
Arg Cys His Phe Arg Trp Xaa
1 5
<210>189
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=homocysteine
<400>189
Arg Cys His Phe Arg Trp Xaa
1 5
<210>190
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉the 4-fluorine replaces, the D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=homocysteine
<400>190
Arg Cys His Phe Arg Trp Xaa
1 5
<210>191
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉4-chlorine replaces, the D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=homocysteine
<400>191
Arg Cys His Phe Arg Trp Xaa
1 5
<210>192
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(9)..(9)
＜223〉Xaa=homocysteine
<400>192
Tyr Arg Cys Glu His Phe Arg Trp Xaa
1 5
<210>193
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=homocysteine
<400>193
Xaa His Phe Arg Trp Xaa
1 5
<210>194
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=homocysteine
<400>194
Arg Xaa His Phe Arg Trp Xaa
1 5
<210>195
<211>7
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(2)..(7)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉D type
<220>
<221>MOD_RES
<222>(7)..(7)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(7)..(7)
＜223〉Xaa=homocysteine
<400>195
Arg Xaa His Phe Arg Trp Xaa
1 5
<210>196
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(8)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉D type
<220>
<221>MOD_RES
<222>(8)..(8)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(8)..(8)
＜223〉Xaa=homocysteine
<400>196
Tyr Arg Xaa His Phe Arg Trp Xaa
1 5
<210>197
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(3)..(9)
<220>
<221>MISC_FEATURE
<222>(3)..(3)
＜223〉Xaa=homocysteine
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉D type
<220>
<221>MOD_RES
<222>(9)..(9)
＜223〉amidatioon
<220>
<221>MISC_FEATURE
<222>(9)..(9)
＜223〉Xaa=homocysteine
<400>197
Tyr Arg Xaa Glu His Phe Arg Trp Xaa
1 5
<210>198
<211>6
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MOD_RES
<222>(1)..(1)
＜223〉acetylation
<220>
＜221〉disulphide
<222>(1)..(6)
＜223〉S-CH2-S bonding
<220>
<221>MOD_RES
<222>(3)..(3)
＜223〉D type
<220>
<221>MOD_RES
<222>(6)..(6)
＜223〉amidatioon
<400>198
Cys His Phe Arg Trp Cys
1 5
<210>199
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=Arg, Tyr-Arg, Tyr-β-Arg, or lack
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉the modified aminoacid of Xaa=comprises Arg, citrulline,
Homoarginine, Leu, Lys, N-isopropyl-Lys, nor-leucine, ornithine,
Or Val
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉the modified group of Xaa=comprises Tyr-Arg, the Tyr-citrulline,
Cya-Arg, the Tyr-homoarginine, Tyr-1-β-homoarginine, Tyr-Lys,
Tyr-Ser, or Tyr-Val
<220>
＜221〉disulphide
<222>(2)..(8)
＜223〉S-S or S-CH2-S disulphide bridges
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=Cys, homocysteine, or deaminizating cysteine; Can be D or L type
<220>
<221>MISC_FEATURE
<222>(3)..(3)
<223>Xaa＝Glu，Gln，Asp，Asn，Ala，Gly，Thr，Ser，Pro，Met，Ile，Val，
Arg, His, Tyr, Trp, Phe, Lys, Leu, cysteic acid, or lack
<220>
<221>MISC_FEATURE
<222>(4)..(4)
＜223〉Xaa=His, modified His, or modified Ala; D or L type
<220>
<221>MISC_FEATURE
<222>(5)..(5)
＜223〉Xaa=Phe, modified Phe, or modified Ala; D or L type
<220>
<221>MISC_FEATURE
<222>(6)..(6)
＜223〉Xaa=Arg or modified Arg; D or L type
<220>
<221>MISC_FEATURE
<222>(8)..(8)
＜223〉Xaa=Cys, homocysteine, or modified cysteine or homocysteine (as amide, alcohol, or penicillamine)
<220>
<221>MISC_FEATURE
<222>(9)..(9)
＜223〉Xaa=Ser-Pro-NH2, Lys-Pro-NH2, Ser-OH, Ser-Pro-OH, Lys-OH, Ser alcohol, Ser-Pro alcohol, Arg-Phe NH2, Glu-NH2, or lack
<400>199
Xaa Xaa Xaa Xaa Xaa Xaa Trp Xaa Xaa
1 5
<210>200
<211>8
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=Arg, Tyr-Arg, Tyr-β-Arg, or lack
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉the modified aminoacid of Xaa=comprises Arg, citrulline,
Homoarginine, Leu, Lys, N-isopropyl-Lys, nor-leucine, ornithine,
Or Val
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉the modified group of Xaa=comprises Tyr-Arg, the Tyr-citrulline,
Cya-Arg, the Tyr-homoarginine, Tyr-1-β-homoarginine, Tyr-Lys,
Tyr-Ser, or Tyr-Val
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=Cys or homocysteine
<220>
<221>MISC_FEATURE
<222>(3)..(3)
<223>Xaa＝Glu，Gln，Asp，Asn，Ala，Gly，Thr，Ser，Pro，Met，Ile，Val，
Arg, His, Tyr, Trp, Phe, Lys, Leu, cysteine, or lack
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉His can be optional replacement, D or L type
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉Phe can be optional replacement, D or L type
<220>
<221>MISC_FEATURE
<222>(8)..(8)
＜223〉Xaa=Cys, homocysteine, or modified cysteine or homocysteine such as amide
<220>
<221>MISC_FEATURE
<222>(9)..(9)
<223>Xaa＝Ser-Pro-NH2，Lys-Pro-NH2，Ser-OH，Ser-Pro-OH，Lys-OH，Ser
Alcohol, Ser-Pro alcohol, Arg-Phe-NH2, Glu-NH2, or lack
<400>200
Xaa Xaa Xaa His Phe Arg Xaa Xaa
1 5
<210>201
<211>9
<212>PRT
＜213〉artificial
<220>
＜223〉synthetic construct
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉Xaa=Arg, Tyr-Arg, Tyr-β-Arg, or lack
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉the modified aminoacid of Xaa=comprises Arg, citrulline,
Homoarginine, Leu, Lys, N-isopropyl-Lys, nor-leucine, ornithine,
Or Val
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉the modified group of Xaa=comprises Tyr-Arg, the Tyr-citrulline,
The Tyr-homoarginine, Tyr-1-β-homoarginine, Tyr-Lys, Tyr-Ser, or
Tyr-Val
<220>
＜221〉disulphide
<222>(2)..(8)
<220>
<221>MISC_FEATURE
<222>(2)..(2)
＜223〉Xaa=Cys or homocysteine
<220>
<221>MISC_FEATURE
<222>(3)..(3)
<223>Xaa＝Glu，Gln，Asp，Asn，Ala，Gly，Thr，Ser，Pro，Met，Ile，Val，
Arg, His, Tyr, Trp, Phe, or lack
<220>
<221>MOD_RES
<222>(4)..(4)
＜223〉His can be optional replacement, D or L type
<220>
<221>MOD_RES
<222>(5)..(5)
＜223〉Phe can be optional replacement, D or L type
<220>
<221>MISC_FEATURE
<222>(8)..(8)
＜223〉Xaa=Cys, homocysteine, or modified cysteine or homocysteine such as amide
<220>
<221>MISC_FEATURE
<222>(9)..(9)
<223>Xaa＝Ser-Pro-NH2，Lys-Pro-NH2，Ser-OH，Ser-Pro-OH，Lys-Pro-OH，
Arg-Phe-NH2, Glu-NH2, or lack
<400>201
Xaa Xaa Xaa His Phe Arg Trp Xaa Xaa
1 5
Claims (23)
1. the chemical compound of following formula:
And officinal salt, wherein
W is Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya or shortage,
R
1Be-H ,-C (O) CH
3,-C (O) (CH
2)
1-4CH
3,-C (O) (CH
2)
1-4NHC (NH) NH
2, Tyr-β Arg-, Ac-Tyr-β-hArg-, glucose acidic group-Tyr-Arg-, Ac-diamino bytyry-, Ac-two alanyl-, N-propiono, N-bytyry-, the N-valeryl-, N-methyl-Tyr-Arg-, N-glutaryl-Tyr-Arg-, N-succinyl-Tyr-Arg-, R
6-SO
2NHC (O) CH
2CH
2C (O)-, R
6-SO
2NHC (O) CH
2CH
2C (O) Arg-, R
6-SO
2NHCH
2CH
2CH
2C (O)-, C
3-C
7Naphthene base carbonyl, phenyl sulfonyl, C
8-C
14Bicyclic aryl sulfonyl, phenyl-(CH
2)
qC (O)-, C
8-C
14Bicyclic aryl-(CH
2)
qC (O)-,
R
2Be-H ,-NH
2,-NHC (O) CH
3,-NHC (O) (CH
2)
1-4CH
3,-NH-TyrC (O) CH
3, R
6SO
2NH-, Ac-Cya-NH-, Tyr-NH-, HO-(C
6H
5)-CH
2CH
2C (O) NH-or CH
3-(C
6H
5)-C (O) CH
2CH
2C (O) NH-;
R
3Be C
1-C
4Straight or branched alkyl, NH
2-CH
2-(CH
2)
q-, HO-CH
2-, (CH
3)
2CHNH (CH
2)
4-, R
6(CH
2)
q-, R
6SO
2NH-, Ser, Ile,
Q is 0,1,2 or 3;
R
6Be phenyl or C
8-C
14Bicyclic aryl;
M is 1 or 2;
N is 1,2,3 or 4;
R
9Be (CH
2)
pOr (CH
3)
2C-;
P is 1 or 2;
R
10Be NH-or disappearance;
R
7Be randomly to use R
4The 5-that replaces or 6-unit's heteroaryl or 5-or 6-unit hetero-aromatic ring;
R
4Be H, C
1-C
4Straight or branched alkyl, phenyl, benzyl or (C
6H
5)-CH
2-O-CH
2-;
R
8The benzyl ring or the cyclohexyl that are phenyl, randomly replace with X;
X is H, Cl, F, Br, methyl or methoxy;
R
11Be-C (O) or-CH
2
R
5Be-NH
2,-OH, glycinol, NH
2-Pro-Ser-, NH
2-Pro-Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-,-Ser alcohol ,-Ser-Pro alcohol ,-Lys-Pro alcohol, HOCH
2CH
2-O-CH
2CH
2NH-, NH
2-Phe-Arg-, NH
2-Glu-, NH
2CH
2RCH
2NH-, RHN-or RO-, wherein R is C
1-C
4The straight or branched alkyl; And
L is-S-S-or-S-CH
2-S-.
2. the chemical compound of following formula:
And officinal salt, wherein
W is singly-bound, Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp or Phe;
R
1Be-H ,-C (O) CH
3,-C (O) (CH
2)
1-4CH
3,-C (O) (CH
2)
1-4-NHC (NH) NH
2, Tyr-β Arg, glucose acidic group-Tyr-Arg, Ac-Dab, Ac-Dap, N-succinyl-Tyr-Arg, N-propiono, N-valeryl, N-glutaryl-Tyr-Arg, N-bytyry,
Or
Wherein
R
2Be-H ,-NH
2,-NHC (O) CH
3,-NHC (O) (CH
2)
1-4CH
3Or-NH-TyrC (O) CH
3
R
3Be C
1-C
4Straight or branched alkyl, Ser, Ile,
Or
Q is 0,1,2 or 3;
M is 1 or 2;
P is 1 or 2;
R
4Be H or C
1-C
4The straight or branched alkyl;
X is H, Cl, F, Br, methyl or methoxy; And
R
5Be-NH
2,-OH, glycinol ,-Ser-Pro-NH
2,-Lys-Pro-NH
2,-Ser-OH ,-Ser-Pro-OH ,-Lys-Pro-OH-Arg-Phe-NH
2,-Glu-NH
2,-NHR or-OR, wherein R is C
1-C
4The straight or branched alkyl.
3. the described chemical compound of claim 2, the condition of described chemical compound is especially with R
2=Tyr, R
3=Arg, W=Glu, R
4=H, X=H, m=1, p=1 and R
5=NH
2Combination get rid of.
4. the chemical compound of following formula:
And officinal salt, wherein
W is Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya or shortage;
R
1Be-H ,-C (O) CH
3,-C (O) (CH
2)
1-4CH
3,-C (O) (CH
2)
1-4NHC (NH) NH
2, Tyr-β Arg-, Ac-Tyr-β-hArg-, glucose acidic group-Tyr-Arg-, Ac-diamino bytyry-, Ac-two alanyl-, N-propiono, N-bytyry-, the N-valeryl-, N-methyl-Tyr-Arg-, N-glutaryl-Tyr-Arg-, N-succinyl-Tyr-Arg-, R
6-SO
2NHC (O) CH
2CH
2C (O)-, R
6-SO
2NHC (O) CH
2CH
2C (O) Arg-, R
6-SO
2NHCH
2CH
2CH
2C (O)-, C
3-C
7Naphthene base carbonyl, phenyl sulfonyl, C
8-C
14Bicyclic aryl sulfonyl, phenyl-(CH
2)
qC (O)-, C
8-C
14Bicyclic aryl-(CH
2)
qC (O)-,
R
2Be-H ,-NH
2,-NHC (O) CH
3,-NHC (O) (CH
2)
1-4CH
3,
-NH-TyrC (O) CH
3, R
6SO
2NH-, Ac-Cya-NH-, Tyr-NH-, HO-(C
6H
5)-CH
2CH
2C (O) NH-or CH
3-(C
6H
5)-C (O) CH
2CH
2C (O) NH-;
R
3Be C
1-C
4Straight or branched alkyl, NH
2-CH
2-(CH
2)
q-, HO-CH
2-, (CH
3)
2CHNH (CH
2)
4-, R
6(CH
2)
q-, R
6SO
2NH-, Ser, Ile,
Q is 0,1,2 or 3;
R
6Be phenyl or C
8-C
14Bicyclic aryl;
M is 1 or 2;
P is 1 or 2;
R
4Be H, C
1-C
4Straight or branched alkyl, phenyl, benzyl or (C
6H
5)-CH
2-O-CH
2-;
X is H, Cl, F, Br, methyl or methoxy; And
R
5Be-NH
2,-OH, glycinol, NH
2-Pro-Ser-, NH
2-Pro-Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-,-Ser alcohol ,-Ser-Pro alcohol ,-Lys-Pro alcohol, HOCH
2CH
2-O-CH
2CH
2NH-, NH
2-Phe-Arg-, NH
2-Glu-, NH
2CH
2RCH
2NH-, RHN-or RO-, wherein R is C
1-C
4The straight or branched alkyl.
5. the described chemical compound of claim 4, wherein
W is Glu or shortage;
R
1Be H-, Ac-, Arg-, Ac-Arg-or Ac-D-Arg-;
M is 1 or 2;
P is 1; And
R
5Be NH
2Or OH.
6. the described chemical compound of claim 4, wherein W is Glu; R
1Be Ac-D-Arg-; M is 1; P is 1; And R
5Be NH
2
7. the described chemical compound of claim 4, wherein W lacks; R
1Be Ac-; M is 2; P is 1; And R
5Be NH
2
8. the described chemical compound of claim 4, wherein W is Glu; R
1Be Ac-Arg-; M is 1; P is 1; And R
5Be NH
2
9. the described chemical compound of claim 4, wherein W lacks; R
1Be H; M is 2; P is 1; And R
5Be NH
2
10. the described chemical compound of claim 4, wherein W lacks; R
1Be Arg-; M is 2; P is 1; And R
5Be OH.
11. chemical compound, it is selected from the 1-198 chemical compound.
12. the described chemical compound of claim 11, wherein chemical compound is 48,52,132,137 or No. 155 chemical compounds.
13. the described chemical compound of claim 12, wherein chemical compound is Ac-D-Arg-ring [Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH
2
14. the described chemical compound of claim 12, wherein chemical compound is Ac-ring [hCys-His-D-Phe-Arg-Trp-Cys]-NH
2
15. pharmaceutical composition, it comprises pharmaceutically suitable carrier and at least a as any described chemical compound among the claim 1-14.
16. be used for the method for exciting MC4 receptor, described method comprises that the patient to needs uses the step of any described chemical compound among at least a claim 1-14 of pharmacy effective dose.
17. the method for treatment of obesity in mammal, described method comprise the step to any described chemical compound among at least a claim 1-14 of the administration pharmacy effective dose of needs.
18. the method for treatment diabetes in mammal, described method comprises the step to any described chemical compound among at least a claim 1-14 of the administration pharmacy effective dose of needs.
19. treat the method for male and/or female sexual dysfunction in mammal, described method comprises the step to any described chemical compound among at least a claim 1-14 of the administration pharmacy effective dose of needs.
20. as any described chemical compound among the claim 1-14 of medicine.
21. the purposes as chemical compound as described among the claim 1-14 any is used to prepare the medicine of treatment of obesity.
22. the purposes as chemical compound as described among the claim 1-14 any is used to prepare the medicine for the treatment of diabetes.
23. the purposes as chemical compound as described among the claim 1-14 any is used to prepare the handicapped medicine of therapeutic.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47974003P | 2003-06-19 | 2003-06-19 | |
| US60/479,740 | 2003-06-19 | ||
| US60/557,347 | 2004-03-29 | ||
| US60/570,737 | 2004-05-13 | ||
| US60/570,676 | 2004-05-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1809372A true CN1809372A (en) | 2006-07-26 |
Family
ID=36840899
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480017178 Pending CN1809372A (en) | 2003-06-19 | 2004-06-17 | Melanocortin recptor 4(MC4) agonists and their uses |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1809372A (en) |
| ZA (1) | ZA200510189B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011153817A1 (en) * | 2010-06-10 | 2011-12-15 | 中国人民解放军军事医学科学院毒物药物研究所 | Cyclopeptides used as melanocortin-4 receptor agonist |
| CN105037502A (en) * | 2009-06-08 | 2015-11-11 | 帕拉丁科技公司 | Melanocortin receptor-specific peptides |
| CN111718408A (en) * | 2020-07-06 | 2020-09-29 | 成都圣诺生物制药有限公司 | Preparation method of Setmelanotide |
-
2004
- 2004-06-17 CN CN 200480017178 patent/CN1809372A/en active Pending
-
2005
- 2005-12-14 ZA ZA200510189A patent/ZA200510189B/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037502A (en) * | 2009-06-08 | 2015-11-11 | 帕拉丁科技公司 | Melanocortin receptor-specific peptides |
| WO2011153817A1 (en) * | 2010-06-10 | 2011-12-15 | 中国人民解放军军事医学科学院毒物药物研究所 | Cyclopeptides used as melanocortin-4 receptor agonist |
| CN111718408A (en) * | 2020-07-06 | 2020-09-29 | 成都圣诺生物制药有限公司 | Preparation method of Setmelanotide |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200510189B (en) | 2007-04-25 |
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