MXPA97007904A - Analogues of the release factor of the hormone of growth - Google Patents
Analogues of the release factor of the hormone of growthInfo
- Publication number
- MXPA97007904A MXPA97007904A MXPA/A/1997/007904A MX9707904A MXPA97007904A MX PA97007904 A MXPA97007904 A MX PA97007904A MX 9707904 A MX9707904 A MX 9707904A MX PA97007904 A MXPA97007904 A MX PA97007904A
- Authority
- MX
- Mexico
- Prior art keywords
- ala
- aib
- leu
- arg
- tyr
- Prior art date
Links
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- 239000007952 growth promoter Substances 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
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- AHIHJODVQGBOND-UHFFFAOYSA-M propan-2-yl carbonate Chemical compound CC(C)OC([O-])=O AHIHJODVQGBOND-UHFFFAOYSA-M 0.000 description 1
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Abstract
The present invention relates to a peptide which is a variant of the human growth hormone releasing factor. The peptide, which contains 23 to 28 amino acid residues, differs from its native counterpart at least in portions 8, 9, 16, 18, 24, 25, 27 and 28 and is potent in stimulating the release of growth hormone.
Description
ANALOGUES OF THE RELEVANT FACTOR OF THE GROWTH HORMONE BACKGROUND OF THE INVENTION Creolone hormone (GH) or soma is a peptide of 191 amino acids secreted by the anterior pituitary gland. Growth hormone itself does not directly promote growth but acts by stimulating the production of growth factors such as, for example, somato-edins produced by the liver. The final effect of growth hormone is to stimulate the growth of the skeleton, connective tissues, muscles and viscera. Inadequate levels of growth hormone in children cause growth retardation. They also cause a delayed development of secondary sexual characteristics, an affected development of the larynx as well as hypoglycemia. The production of growth hormone is under the control of release and inhibition factors secreted by the hypothalamus. The primary influence of release is effected by the growth hormone releasing factor
(GRF), produced primarily in the arcuate nucleus of the hypothalamus and transported to the pituitary gland by the portal circulation. Substantial efforts have been made to develop synthetic analogs of GRF more effectively than native GRF to stimulate the growth hormone development. For human GRF (hGRF) and GRF structures from other sources, see Wehrenberg, W.B., et al., Hormone Res., 24:82 (1986). COMPENDIUM OF THE INVENTION The invention relates to peptides encompassed by the following generic formula:
ßu-A? Al6-Leu-Al-Ala-Arg-A21-A-2-L «u-Aa4-A25- wherein Al is the D or L isomer of an amino acid selected from the group consisting of Tyr and His, or imin; A2 is Aib, or the D or L isomer of an amino acid selected from the group consisting of Ala, N-Me-Ala, and Arg; A8 is Ala, Aib, or Gly; A9 is Ala, Aib, or Gly; A10 is Phe or p-X-Phe where X is OH, CH3 or a halogen (for example, F, Cl, Br, or I); A12 is Lys or Népsi lon-X-Lys where X is C1-C6 alkyl, C1-C6 acyl, C1-C6 hydroalkyl, or C2-C6 hydroxy acyl; A15 is Ala, Aib, or Gly; A16 is Ala, Aib, or Gly; AIS is Ala, Aib, or 61y; A21 is Lys or Népsi lon-X-Lys where X is Cl-C¿ alkyl > , C1-C6 acyl, hydroxyalkyl Cl-C ?, or C2-C6 hydroxy acyl; A22 is Ala, Aib, Gly, Leu, Lie, Val, Nle, Nva, or Abu;
A24 is Ala, Aib, Gaba, Gly or His; A25 is Ala, Aib, Gaba, Gly, His, or else it is deleted; A26 is Ala, Aib, Gaba, Gly, His, or is deleted; A27 is Ala, Aib, Gly, Leu, Lie, Val, Nle, Nva, Abu, Gaba, Beta-Ala, Ava, His, or else it is deleted; A28 is Aib, the D isomer or either L of Ala, Gaba, His, or is deleted; each of R 1 and R 2 is independently H, Cl-C 12 alkyl, C 7 -C 20 phenylalkyl, C 1 -C 20 naphthalene, C 1 -C 12 hydroxyalkyl, C 7 -C 20 hydroxyphene, C 1 -C 20 hydrohaloalkyl, or C0E1, where El is C1-C12 alkyl, C7-C20 phenylalkyl, naphthi C11-C20 alkyl, C1-C12 hydroxyalkyl, C7-C20 hydroxyphenyl, or C11-C20 hydroxynaphtylalkyl; and R3 is OH, NH2, C1-C12 alkoxy or NH-Y-CH2 »Z where Y is a portion of C1-C12 hydrocarbon (divalent, for example, straight or branched alkyl group) and Z is H, OH, C02H , or C0NH2; or a pharmaceutically acceptable salt thereof.
Below are examples of the peptides of this invention encompassed by the following formulas:
H ^ Tyr-D-Ala »Mp-Al * -Il» -? > h »- ^ * - Xi -Al * -Tyr-Arß-LyB-V * l- / * ßu-? ia-? la-'l? u-lAib-Ala-Arg- and» -? X - Lß -Ail > -Al »-M * -
(Analogue No. 1),
R Tyr-D-Ala-Aβp-Ala-Δle-Ph «-Thr-ib-Ala-Tyr-Ar ?t- yß-Va1- / Lßu-All-Ala-tau-Aβ-Aia-Arg-t. yB-AXa-Lßw-Aib-Al «-Ala- MH (CH2) jCHj
(Analogous No. 2), B Tyr-D-Ai »'- Aßp-Ala-Xlβ) -Phe-Thr-Aib-Ala-Tαr-Arg-Lyß-V * l- / HI-ra-Ala- Ala-l? Tt-Aib-Ala-Arí-tyB-Ala-Lß -Alb-Ala-Ala-A1 * -NH2
(Analogue No. 3),
H \ Ty * -D-Ala-Aβ? -Ala-Ile-Phe-Thr-ALb-Al.a-Tyr-Art3-tyß) -Val- / H fcßu-Ala-Alß-ßu-Ai-b-Ala -Arg-Lyß-Ala-Lßu-Aib-Ala-AXa- (Analogue No. 4), B D-ili »-A *? - Ala-Ile-'Phß-Thr-Aib-Ala-Tyr-Arg-yß -Val- ßu- / H? T > Ala-Ala-l? U-Aib-Ala-Arg-Lyß-Ala-Lßu-Alb-Ala-Ala-l? U-NH2
(Analogue No. 5), 8 Tyr-D-Ala-Aßp-Al "-Ilβ-Pb * -Xbr-Aib-Ala-Tyr-Arg- and" -Val- / eu-Ala-Ala-Lßu-Aib- Ala-Artg-tyß-Ala-Lßu-Aib-Ala-Ala- (Analogue No. 6), H ^ t and -D-Ala-Aap-Al * -Ilß-Phß-T rA -Ala-Tyr-Arß- I.yß-Val- / t -Ala-Ala-l? U-Ala-Ala-Artj-lya-Ala-ßu-Ala-Ala-? La- Ala? La-MH2
(Analogous No. 7), B XTyr-D-Ala-Aßp-Al »-ll» - »be-Tí? R-AJ-b-Ala-Tyr-Arg-yss-Val- / H taw-j a- Ala-l-ßu-Aib-Ala-Arg-Iyß-Ala-Lßu-Aib-Ala-Ala-HH
(Analogue No. 8), H yr-D-Ala-Aa? -Ala-21 * -Phe-thr-Aib-Ala-Tyr-Arß-Lyß-Val- / H ßu-Ala-Ala-LßU-Aib- Ala-Arg-Lyß-AXa-Leu-Ala-Ala-Ala-Ala-KHj
(Analogue No. 9), H \ AXa-Aap-Ala-lle-Phe'T r-Aib-Ala-Tyr-Arg-LyH-val-au-Hpp Ala-Ala-Lßu-Aib-Ala-Arg-yß -Ala- eu-Aib-Ala-Ala-Mlß- Ala-M? J
(Analogue No. 10, SEQ ID N0: 8), H ^ Xyy-DA a-Aβp-A a-1 Xe-Phß-Thr -Aib-Ala-Tyr-Arg-I, and a-Val - / 8 teu -Ala-Ala-ßu-Aib-AXa-Arg-tya-AXa-tßu-Aib-AXa- Ala-Caba-HHj
(Analogue No. 11),
\ AXa-Aßp-AXa-IX -Phe-thr-Aib-AXa-Tyr-Arg-Lya-Val-l? U-AXa- Hpp Ala-L? U-Aib-Ala-Arg-yss-AXa-Lßu-Aib- Aia-AXa-Cabam (Analogue No. 12, SEQ ID N0: 1),
B \ Tyr-D-Aia-Aap-AX * -Ha-Phß-X-ir-Aib-Ala-Tyr-A-fg-Ly > -VaX- * - B Ala-Ala-l? U-Atb-AXa-Arg-Lyß-Ala-i? U-Aib-Ala-AXa-Lßu-Ala- (Analogue No. 13),
? X AXa-A «» - AX «-lXa- he-Thr-Alb-AXa-'Pyr-Arg- y.-Vi-Lß -AXa- / HPP Ala-l * ü-Alb-Aia-Arg-l, and - AXa-i-eu-Aib-Ala-Ala-AXa-MH2
(Analogue No. 14, SEQ ID NO: 2), B ^ Iß-Xβp-Ala-IXβ-Pbβ-Thr-Aib-AXa-Phe-Arg-yß-Vai-Leu-Ala- / H p A ^ .I ^ u-AiB-AXa-Arg-tyß-Ala-ßu-Ai-b-Ala-Ala-Ala-KHj
(Analogue No. 15, SEQ ID N0: 3)
B ja.a-Aap-AXa-Ile-Phe-Thr-Aib-Ma-Tyr-Arg-LyB-Val-eu? Lfc- / W Ala-X? U-Aib-AXa-A? Rg-Lyß-Ala -1-ßu-Aib-AXa-AXa-rfHj
(Analogue No. 16, SEQ ID N0: 4), B \ Ala-? Tp-AXa-IX * -Phe-Thr-? Ib-Ala-Tyr-Arg-yi-V4l- eu-AXa- Hpp AXa- ßu -Aib-AXa-Arg-l-yB-AXa-Lßu-Ai-b-AXa-AXa-NH < CH2 > jCBj
(Analogue No. 17, SEQ ID N0: 5),
B AXa-ABp-AXa-Ilß-Phß-thr-Aib-Ala-Tyr-Arg-tyB-Val-Bu-Ala-
/ H P Ala- eu-Aib-AXa-Arg-Lyß-AXa-l? U-Aib-Ala-irajlCHjJjCHj
(Analogue No. 18, SEQ ID NO: 0), B ^ Iyr, 0-AXa-ABp-Ala-XXβ-Phe-TÍ-r-Aib-AXa-Tyr-Arg-tyB-vaX- / B eu-Ala -AXa-Lßu-Aib-AXa-Aíg-Lyß-AXa-Lß -AXa-AXa-Ala- HHjtCB ^ jCBs
(Analogue No. 19), B \ Tyr-D-AXa-Aßp-AXa-Il «-Ph« r-thr-Aib-Ala-Tyr-Arg-LyB-Val-H i? U-Ala-Ala-Leu -Aib-AXa-Arg-Lyß-Ala-Lßu-Ala-Ala-A-tK2 (ñ2) í? C 3
(Analogue No.20), H Tyr-D-Ala-Aβp-Ala-Ilé-Phß-Thx-Aib-Ala-Tyr-Arg-yß-Val-Bβ-Ala-Ala-Leo-AXb-Ala-Arg -Lyß-Ala-Lßu-Ala-AXa-NBj (Analog No.21)
H \ Tyr »D-Ala-ABp-Ala-Ile-Phß-thr-Alb-Ala-Tyr-Axg-yß-Val-B
X ?? - AXa-Aia- eu-Aib-Ala-Arg-Lyß-Ala-L * u-AXa-NH,
(Analogue No.22),
H \ AXa-Aβp-Ala-Ilβ-Pbß-th * -Aib-Ala-yr-Arg-LyB-VaX-ßu-AXa-Bpp ALa-L »u-Aib-AXa-Arg-tyf-Ala-Lβ) u-Ala-NH2
(Analogue No. 23, SEQ ID N0: 7),
B Tyr-P-Ala-Aßp-Ala-IX «-Phß-Thr-Ala-AXa-Tyr-A? GI, and? -Val- / B tßu-AXa-AXa- eu-Ala-AXa-Arg-Lyß -AXa-Lßu-AXa-Ala-AXa-Ala-KBj,
a tyr-D-AXa-Aβp-AXa-He-Pbe-? hr-AXa-Ala-tyr-Ajrg-X > yß-Val- / B l? u-Ma-Ala-Lßu-Al * -Ala-Arg-Ly * -? la-l? U-? la-AXa-Ala-NH2, and -Ala-í 2
H Tyx-D-? La-Aßp-Ala-Ile-Phe-Thr-Aib-Ala-Tyr-Arg-LyB-Val- / H Lßu-AXa-Ala-LéU'Aib-AXa-Arg-tya-Ala- Leu-Aib-AXa-Ala-ßaba- • «. (CHjj jcaij
B Tyr-D-AXa-Aßp-Ala-lXß-Phß-Thr-Aib-Ala-Tyr-Arg-Lyß-VaX- / l? U-Ala-Ala-I? -Aib-Ala-Arg-LyB-Ala-Leu »Aib-AXa-AXa« -Caba- KH (CH2) jCH3
B? Yr-.D-AXa-A * p-AXa-lXβ-Phß-Thr-Aib-Ala-Tyr-Arg-Lyß-VaX- / l.ßu-Ala-AXa-I-eu-Aib-Ala Arg-Lyß-Ala -. Eu-AXa-Al.a-Ala-Gaba-HH2.
(Aná l ogo No. 24),
B ^ lyr-D-AXa-Aβp-AXa-IX »-Pbe-Thí-Alb-AXa-Phe-Arg-I.yi-Val-Lau- -
* Aia-AXa-l? «- Alb-AXa-Aeg- and B-AXa-Lßu-Al4-AXa-Ala-C - ba-ira2
(Analogue No. 25)
B ^ Tyr-D-AXa-Aßp-Ala-xXβ-Phß-thr-Aib-Ala-Tyr-Arg-LyB-Val-l? U- / Alß-Aia-Lßu-Aib-AXa-Arg-I.B -Ala-Lßu-AÍb-Ala- <; aba-WH2 (Analogue No. 26) With the exception of the amino acid of the N-terminus, Gaba, beta-Ala, and AV ?, all'3 abbreviations' for example, Ala or? "of amino acids of this ion present refer to the structure of an alpha-amino acid residue -NH-CH (R) -CQ-, where R is an amino acid side chain (for example, CH3 for Ala). Similar structures are foreseen for non-alpha-amino acid residues Gaba, beta-Ala, and Ava. On the other hand, for e) N-terminal amino acid, the abbreviation represents the structure of -N-CH (R) -CO-, where R is a side chain determinant of an amino acid. N-Me-Ala, Nle, Nva, Ab ?, Gaba, beta-Ala, Ava, and Aib are respective abbreviations of the following alpha-amino acids: N-methyl-alanine, norleucine, norvaline, acid to fa-a inobut í 1 ico, gamma-aminobutyric acid (4-aminobutanoic acid), beta-alanine (3-aminoproponic acid), delta-aminovaleric acid (5-aminopentanoic acid), and alpha-aminoisobutyrate. Népsi lon-X-Lys represents the amino acid Lys where a hydrogen of the amino group epsillan is replaced by X. In cases where the amino acid residue is optically active, it is the L isomer that is represented unless specified contrary. Likewise, in the above generic formula, hydroxyalkyl, hydroxyacyl, hydroxy eni 1 -alkyl, and hydroxynaphthalkyl can contain from 1 to 4 hydroxy ituents, and CO represents -C = 0 * E1.
Examples of -C = 0- include, but are not limited to, p-hydroxyphene lpropioni (or Hpp, ie, -C = 0-CH2-Ch2-C6H4-0H) and phenolpropioni lo. The peptides of the present invention can be used to stimulate the release of growth hormone in a subject (a mammal such as, for example, a human patient). Accordingly, the peptides are useful for the treatment of physiological conditions in which growth hormone is beneficial, for example, patients who do not have an adequate production of endogenous growth hormone as for example the elderly. The peptides of the present invention can be used to stimulate linear growth in patients of short stature, for example, children with growth hormone deficiency. Other uses include growth promoter stimulus, (eg, skeletal, cellular, and organ growth), protein metabolism, carbohydrate metabolism, lipid metabolism, mineral metabolism, and connective tissue metabolism, all of which carry a Increased physical strength and greater well-being. The peptides of the present invention may also be employed in the treatment of catabolic states (eg, recovery from infection, surgical intervention, and malnutrition), the stimulation of immune function, and the increase of natural sleep patterns. The peptides of the present invention can also be used to stimulate the growth of animals (eg, cattle). The peptide? of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, the salts formed with organic acids (for example, acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluene sulfonic or pamoic acids), inorganic acids (eg. for example, hydrochloric acid, sulfuric acid, or phosphoric acid), polymeric acids (for example, tannic acid, carboxymethylcellulose, polylactic acids, pololytic polyol or copolymers of polylactic-glycolic acids). A therapeutically effective amount of a peptide of this invention and a pharmaceutically acceptable carrier substance (eg, magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a micelle) together form a therapeutic composition (e.g. , a pill, tablet, capsule, or liquid) for administration (for example, oral, intravenous, transdermal, pulmonary, vaginal, subcutaneous, nasal, iontaphoric or intrat aquea 1 administration) to a subject requiring the peptide. The pill, tablet or capsule may be coated with a substance capable of protecting the composition against gastric acid or intestinal enzymes in the stomach of the patient for a sufficient period of time to allow the composition to pass without being digested in the patient. small intestine of the patient. The therapeutic composition may also be in the form of a biodegradable or non-biodegradable extended release formulation for subcutaneous or intramuscular administration. See, for example, U.S. Patent Nos. 3,773,919 and 4,767,628 as well as PCT Application No. WO 94/00148. It can also be obtained to obtain a continuous administration using a pump that can be implanted or an external pump (for example, pump INFUSAI (mr)), to administer the therapeutic composition. The peptide can be administered before the patient lies down. The dose of a peptide of the present invention for the treatment of the aforementioned diseases or disorders varies according to the form of administration, the age and the body weight of the patient, and the condition of the patient to be treated, and the final decision of the patient. doctor or veterinarian. Such amount of peptide in accordance with that determined by the physician or veterinarian is referred to herein as an "effective therapeutic amount". Also contemplated within the scope of this invention is a peptide encompassed by the above generic formula for use in the treatment of diseases or disorders associated with growth hormone deficiencies. The GPF analogs of this invention do not possess the undesirable residues of arginine and methionine at the C-terminus, and therefore this decreases the cost of the synthesis and increases the stability of the peptides. Other features and advantages of the present invention will be apparent from the detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION The synthesis and use of GRF analogs of this invention are within the capacity of a person with certain knowledge in the field. Unless defined otherwise, all technical and scientific terms employed herein have the meaning generally understood by a person with certain knowledge in the subject matter of this invention. Likewise, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. It is considered that one skilled in the art can, based on the present disclosure, employ the present invention to its fullest extent. The following specific modalities should therefore be considered as merely illustrative, and not in any way limiting the rest of the presentation. SYNTHESIS The peptides of the present invention can be prepared by standard solid phase synthesis. See, for example, Stewart, J.M., et al., Solid Phase Synthesis (Pierce Chemical Co., 2nd edition, 1984). Below is a description of how the analog no was prepared. 3. Other peptides of the present invention can be prepared analogously by a person with certain knowledge in the art. A residue of benc ihidri is placed in the ina-pol iestirepo
(Advanced ChemTech, Inc., Louisville, Y) (1.25 g, 0.5 mmol) as a chloride ion in the reaction vessel of an Advanced ChemTech peptide synthesizer (ACT 200) programmed to carry out the following cycle of reactions: (a) methylene chloride; (b) trifluoroacetic acid 33% in methylene chloride (2 times for 1 and 15 min each); (c) methylene chloride; (d) ethanol; (e) methylene chloride; and (f) di isopropi 1-et i lamina at 10 * /. in methylene chloride. The neutralized resin was stirred with Boc-Ala and di isapropi Icarbodi imia (1.5 mmol each) in methylene chloride for 1 hour and the resulting amino acid resin was then cycled through steps (a) to (f) ) in the previous wash program. The following amino acids (1.5 mmol) were then coupled successively by the same procedure: Boc-Ala, Boc-AJa, Boc-Leu, Bac-Ala, Boc-L 3 (2-C1-Z), Boc-Arg (Cough). ), Boc-Ala, Boc-Aib, Boc-Leu, Boc-Ala, Boc-Ala, Boc-Leu, Boc-Val, Boc-Lys (2-Cl-Z), Boc-Arg (Cough), Boc- Tyr (diCIBzl), Boc-Ala, Bac-Aib, Boc-Thr (Bzl), Boc-Phe, Boc-1 le, Boc-Ala, Boc-Asp, Boc-D-Ala, Bac-Tyr (diCIBzl). After removal of the last Boc group and washing (MeOH) and drying in the air at room temperature, the finished resin weighed 2.5 g. The finished resin (2.5 g, 0.5 mmol) was mixed with anisole (5 ml), dithiothreitol (100 mg) and anhydrous hydrogen fluoride (35 ml) at a temperature of 0 ° C and stirred for 45 minutes. The excess hydrogen fluoride was evaporated rapidly in a stream of dry nitrogen. The free peptide was precipitated and washed with ether. The crude peptide was then dissolved in a minimum volume of 2 M acetic acid and eluted on a column (2.5 x 100 cm) of SEPHADEX (mr) G-50 (Pharmacia, Piscataway, NJ) using the same solvent. Fractions that contained a major component, determined by thin-layer chromatography and UV absorption, were then combined, evaporated to a small volume, applied to a column (2.5 x 50 cm) of octadeci silica Isi laño VYDAC (mr ) (10-15 um) (Separations Group, Hesperia, CA), and eluted with a linear gradient of 10-45% acetonitrile in 0.1% trifluoroacetic acid in water. The collected fractions were examined by thin-layer chromatography and by high-performance analytical liquid chromatography and combined to provide maximum purity. Repeated lyophilization of the solution from water provided a fluffy, white powder product. By high performance gas chromatography (HPLC) and thin layer chromatography (TLC) the product was found to be homogeneous. An amino acid analysis of an acid hydrolyzate confirms the composition of the octapeptide. A laser desorption MS gave a molecular weight of 2793 in accordance with the calculated value. The peptide of the present invention can also be prepared by fragment condensation methodology where fragments of peptide are synthesized sep- arately and subsequently coupled. This method generally results in a significantly higher synthesis yield. Preferably, the amino acid of the fragment coupled to the resin is not optically active (e.g., Aib or Gly), thus eliminating the possibility of raceway upon dissociation from the resin. The following is a description of the synthesis of the analog no. 2 using the fragment condensation methodology. Other peptides of the present invention can be prepared analogously with a person with certain knowledge in the art. A copolymer resin of E'oc-Aib-Q-CH3-pol iest i reno-di vi or 1-benzene (Merrifield) (2.5 g, 1.0 mmol) was placed in a reaction vessel of an Advanced peptide synthesizer. ChemTech (ACT 200) programmed to carry out the following cycle of reactions: (a) methylene chloride; (b) tri-fluoroacetic acid at 33 * /. in methylene chloride (2 times for 1 and 15 minutes each); (c) methylene chloride; (d) ethanol; (e) methylene chloride; and (f) di isopropylethi 10% in methylene chloride. The neutralized resin is stirred with Boc-N "* -tosi 1-Arg and di isoprop and Icarbodi ima (1.5 mmol each) in methylene chloride for 1 hour and the resulting amino acid resin was then cycled through the steps (a) to (f) in the previous wash program, then the following amino acids were sequentially coupled
(1.5 mmal) by the same procedure: Boc-Leu, Boc-Ala,
Boc-Lys (Z), Boc-Arg (Cough), and Boc-Ala. The finished resin had a weight of 3.4 g and was suspended in tetrahydrofuran (THF) (50 ml) and saturated 2CP3 (20 ml). The tetrabutyl hydrogensulfate onium (2.8 g) was then added and the mixture was stirred at a temperature of 50 ° C (18 hours). The THF was removed in a vacuum condition and the remaining solution was neutralized with solid K.HS04 with which a buff oil was precipitated. This oil was extracted into n-BuOH and washed repeatedly with water and evaporated to give Boc-Ala-Ar (Tos) -Ly (Z) -Ala-Leu-Aib-OH as a white powder (1.08 g, 0.96 mmol ,?). The material left a TLC mark on Si02 plates (CHC13: MeOH: H20: 45: 10: 1). A cspolmer resin of Boc-Ala-0-CH3-pol iest i reno-divini Ibencena (Merrifield) (1.0 g, 0.5 mmol) was placed in the reaction vessel of an Advanced ChemTech peptide synthesizer programmed to carry after the next reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 15 min each); (c) methylene chloride; (d) ethanol; (e) methylene chloride; and (f) di isopropyl let i 10% film in methylene chloride. The neutralized resin was stirred with Boc-Ala and di isopropylcarbonate (1.5 mmol each) in ethylene chloride for 1 hour and the resulting amino acid resin was then cycled through steps (a) to (a) f) in the aforementioned washing program. Boc-Ala (1.5 mmoles) was then coupled and the resin was subjected to the same cycle of events. The fragment Boc-Ala-Arg (Cough) -Lys (Z) -Ala-Leu-Aib-OH (750 mg, 0.74 mal), above synthesized, was then coupled to this resin in the presence of HBTU (170 m), HOBt (170 mg), and diisopropy let ilamine at .0
% / DMF (3 mi). The following amino acids (1.5 mmoles) were then successfully coupled in the presence of diisopropylcarbonate (1.5 mmoles each / in ethylene chloride for 1 hour: Boc-Aib, Boc-Leu, Boc-Ala, Boc-Ala, Boc -Leu, Boc-Val, Boc-Ly (2-C1-Z), Boc-Arg (Cough), Boc-TyrídiClBzl), Boc-Ala, Boc-Aib, Boc-Thr (Bzl), Boc-Phe, Boc -Ile, Boc-Ala, Boc-Asp (FMOC), Boc-D-Ala, Boc-Tyr (diCIBzl). The completed resin had a weight of 1.95 g. The finished resin (0.96 g, 0.25 mmol) was stirred in 20 ml of a 50:50 mixture of di methyl formamide and n-butylamine (18 h). The reaction mixture was evaporated to an oil to which water was added to obtain a white powder (0.5 g). This powder was subjected to dissociation with hydrogen fluoride and column purification in accordance with that described above. Repeated lyophilization of the solution from water provided the desired product in the form of a white, fluffy powder. By HPLC and TLC the product was found to be homogeneous. The amino acid analysis of an acid hydrolyzate confirmed the composition of the octapeptide. An MS of laser desorption gave a molecular weight of 2736 in accordance with the calculated value. The substituents R1 and R2 of the above generic formula can be fixed on the free amine of the N-terminal amino acid by standard methods known in the art.
For example, alkyl groups, such as for example Cl-C1 alkyl, can be fixed using reductive alkylation. Groups h.dr?, 13 Iqui lo, for example, h? Dro; < The C1-12 can also be fixed using reductive alkylation where the free hydroxy group is protected with a t-butyl ester. Acyl groups, for example C0E1, can be fixed by coupling the free acid, for example, E1C00H, to the free amine of the N-terminal amino acid by mixing the finished resin with 3 molar equivalents of free acid and dusopropylcarbodiimide in chloride of wood for one hour and subjecting the resulting resin to a cycle through steps (a) to (f) in the aforementioned washing program. If the free acid contains a free hydroxy group, for example, p-hydroxy phenylpropionic acid, then the coupling should be carried out with 3 additional molar equivalents of HOBT. The full names of the abbreviations used in the above description of the synthesis are as follows: Boc represents t-but i locarbonyl, Tos represents tosylo, N6-tosyl represents tosyl at the site of guamdils, Z represents benzyloxycarbonyl, Bzl represents bepcila, HBTU represents hexafluorophosphate of (lH-benzotriazol-1-? L) -1, 1, 3,3-tetramet? luronium, HOBT represents hydroxybenzotpazol, and FMOC represents 9-fluoroenilmet loxycarbonyl.
ACTIVITIES Pituitary glands of adult male Charles River CD (mr) rats (Charles River Laboratories, Wil ingtan, MA) conserved under controlled conditions (with light from 0500-1900 h) were dispersed and cultured using an aseptic technique by modification of previously described methods . See Hoefer, M.T., et al., Mol. Cell Endocrinol. 35: 229 (1984); Ben-Jonathan, N., et al., Methods Enzymol. 103: 249 (1983); and Hei an, M.L. et al., Endocrinology 116: 410 (1985). The pituitary glands were removed from decapitated rats, said glands were sectioned, and then placed in a liquid, if iconized, liquid scintillation flask containing 2 ml of 0.2% trypsin (Worthington Biochemicals, Freehold, NJ) in a bicarbonate buffer Krebs-Ringer sterilized by filtration, supplemented with 1% bovine serum albumin, 14 M glucose, a solution of modified Eagle's half vitamins (MEM) as well as amino acids MEM (Gibco Laboratories, Grand Island, NY) (KRBGA). All glass equipment was siliconized in accordance with that described by Sayers et al., Endocrinology (Endocrinology) 88: 1063 (1971). The fragments were incubated in a marla bath for 35 minutes at a temperature of 37 ° C with shaking. The contents of the flasks were then emptied into a scintillation flask containing 2 ml of 0.1% DNase (Sigma Chemical Co., St. Louis, MO) in KRBGA and incubated for 2 minutes at a temperature of 37 ° C with shaking After incubation of the ion, the tissue was decanted into a 15 ml centrifuge tube and allowed to settle in. The medium was discarded, and the sections of pituitary glands were washed 3 times with 1 ml of fresh KRBGA. 2 ml of 0.05% LBI (bean tripsiona inhibitor, orthing Biochemica Is) by gently recovering the fragments and expelling them from a Pasteur pipette if 1 iconized, or opulted.The dispersed cells were then filtered through a wire mesh. nylon with a diameter of 630 μm (Tetko, Elmsford, NY) in a fresh centrifuge tube of 15 ml The first tube was rinsed with an additional 2 ml of LBI that were also transferred to the second tube with filtration. Adas were then further diluted with approximately 15 ml of a sterile filtration Eagle's medium (Gibco) modified according to Dulbecco, which was supplemented with 2.5% fetal calf serum (Gibco), 3% horse serum (Gibco), fresh rat serum 10% (stored on ice for no longer than 1 hour) from the pituitary donors, non-essential amino acids MEM 1% (Gibco), genta icine (10 ng / ml; Sigma) and nystatin (10,000 U / ml, Gibco). The cells were drained in a 50 ml round bottom glass extraction bottle with a large diameter opening. The cells were counted with an acitometer (approximately 2,000,000 cells per gland pi) and randomly placed in dishes at a density of approximately 200,000 cells per well (Co-star group 24, Rochester Scientific Co., Rochester NY). The cells placed in plates were maintained in the aforementioned Dulbecco's medium in a humidified atmosphere of 95% air and 5% C02 at a temperature of 37 < , C for 96 hours. In the preparation of a hormonal challenge, the cells were washed 3 times with medium 199 (Gibco) to remove floating cells and ancient medium. Each dose of a test compound (diluted in test tubes if 1 iconized) was tested in the presence of 0.1 nM of samatostat ina-14 in wells tripled or quadrupled in a total volume of 1 m of medium 199 containing 1% BSA (fraction V, Sigma Chemical Co.). After 3 hours at a temperature of 37 ° C in an atmosphere of air / carbon dioxide (95/5%), the medium was removed and said medium was stored at a temperature of -20 ° C until the test was carried out. to determine the content of growth hormone. The content of growth hormone was determined by standard radioimmunoassay for the growth hormone of the rat. The components for the radioimmunoassay of the growth hormone of the rat including antiserum, growth formula for radioiodination, and reference preparation of growth hormone as well as the procedure were obtained from the National Hormone and Pituitary Program (through Ogden Biosciences Corp., Rockville, MD). The EC50, the concentration of test compound required to simulate 50% of the maximum release of growth hormone, for each test compound, was calculated and normalized with the EC50 value of hGRF (1-29) NH2, which was tested simultaneously in each assay as a reference standard to ensure uniformity of results, using the following formula: normalized EC50 of the test compound = EC50 of hGRFd-29) NH2 / EC50 of the test compound The growth hormone release potency of the standard , hGRF (1-26) NH2, and ten test compounds of the invention appear in the list in Table I. The relative release potency of the growth hormone This was calculated by the formula: Relative Growth Hormone Release Power = Normalized EC50 of hGRF (1-26) NH2 / EC50 Normalized Test Compound As indicated by the data in Table I, GRF analogs of the present invention they are more potent than hGRF (l-26) NH2. For example, analog no.l, analog no.2, and analog no.8, all of which contain 26 amino acid residues, are, respectively, 400, 420, and 130 times more potent than the standard peptide, hBRF (1 -26) NH2, which also contains 26 amino acid residues. TABLE I Compound Relative release of growth hormone hGRF (l-26) NH2 1 Analogue no. 1 400 Analogue no. 2 420 Analogue no. 3 760 Analogue no. 4 470 Analogue no. 5 240 Analogue no. 6 1000 Analogue no. 7 560 Analogue no. 8 130 Analogue no. 9 500 Analogue no. 10 1100 Analogue no. 11 1400 Analogue no. 12 1100 Analogue no. 13 700 Analogue no. 14 610 Analogue no. 15 560 Analogue no. 16 36 Analogue no. 17 330 Analogue no. 18 220 Analogue no. 19 560 Analogue no. 20 550 Analogue no. 21 91 Analogue no. 22 27 Analogue no. 23 27 Analogue no. 24 1800 Analogue no. 25 890 Analogue no. 26 230 OTHER MODALITIES It will be understood that while the invention has been described in relation to the detailed description of a modality, the above discussion is intended to illustrate but not to limit the scope of the present invention which is defined by means of the scope of the invention. appended claims. Other aspects, advantages and modifications are within the claims.
LIST OF SEQUENCES (1) GENERAL INFORMATION: fi) APPLICANT: The Ad inistrators of the Tulane Educational Fund (The Administrators of the Tula e Educational Fund) (ii) TITLE OF THE INVENTION: ANALOGUES OF THE RELEASE FACTOR OF THE HORMONE OF THE GROWTH (iii) NUMBER OF SEQUENCES: 8 (iv) ADDRESS FOR CORRESPONDENCE: (A) RECIPIENT: Fish & Richardson P.C. (B> STREET: 225 Franklin Street (OR CITY: Boston (D) STATE: MA (E) COUNTRY: USA (F) POSTAL CODE: 02110-2804 (v) COMPUTER LEGIBLE FORM: (A) TYPE OF MEANS: Soft disk (B) COMPUTER: compatible with IBM personal computer
(C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) PROGRAM: Patentln Reléase No. 1.0, Version No. 1.30 (vi) DATA OF THE CURRENT APPLICATION: (A) APPLICATION NUMBER: - (B) DATE OF PRESENTATION: 03-Ab i 1-1996 (vi i) DATA FROM THE PREVIOUS APPLICATION: (A) NUMBER OF THE APPLICATION: US 08 / 524,337 (B) DATE OF SUBMISSION: 06-SEPTEMBER-1995 (vii) DATA OF THE PRIOR APPLICATION: ÍA) APPLICATION NUMBER: US 08 / 421,987 (B) SUBMISSION DATE: 14-Ab i 1-1995 (viii) ATTORNEY / AGENT INFORMATION: (A) NAME: Tsao, Y. Rocky (B) ) REGISTRATION NUMBER: 34,053 (C) REFERENCE NUMBER / CEDULA: 00537 / (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 617 / 542-5070 (B) TELEFAX: 617 / 542-8906 (C) TELEX: 200154 (2) INFORMATION FOR SEQ ID N0: 1: (i) CHARACTERISTICS OF SECUENC IA: (A) LENGTH TUD: 25 am and nocides (B) TYPE: amino acid (C) CONFORMATION OF HEBRA: irrelevant (D) TOPOLOGY: both (ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (D) OTHER INFORMATION ON: The amino group of Ala in position 1 is substituted with p-hydroxyphenylpropiani lo; Xaa in each of positions 7, 17 and 23 is an alpha-aminoisobutyl acid; and the Carboxylic group of Ala in position 25 is amidated, for example, CO * NH2 instead of C0 * 0H.
(xi) SEQUENCE DESCRIPTION: SEQ ID N0: 1:
Ala Aßp Ala lie Phé Thr Xaa Ala Tyr Arg lyß VaX leu Ala Ala Le j 5 XO 15 Xaa Ala Arg Lyß Ala Leu Xaa AXa AXa 20 25
(2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 amino acids (B) TYPE: amino acid (C) FABRIC CONFORMATION: irrelevant (D > TOPOLOGY: both (ii) TYPE MOLECULES: protein (ix) CHARACTERISTICS: (D) OTHER INFORMATION: The amino group of Ala in position 1 is substituted with p-hydroxy phenylpropioni, Xaa in each of positions 7, 17 and 23 is an alpha acid -a inoisobuti 1 ico; and the carboxyl group of Ala in the position
26 is amidated, for example, C0 * NH2 instead of CO * OH. (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 2:
AXa Aap Ala lia Phe Thr Xaa AXa Tyr Arg Lyß Val Leu Ala Ala Leu 10 Xaa Ala Arg Lyß Ala Leu Xaa Ala AXa Ala 20 25
(2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 amino acids (B) TYPE: amino acid (OR FABRIC CONFORMATION: irrelevant (D) TOPOLOGY: both (ii) TYPE OF MOLECULE : protein (ix) CHARACTERISTICS: (D) OTHER INFORMATION: The amino group of Ala in position 1 is substituted with p-hidraxifeni lpropiani lo; Xaa in each of positions 7, 17 and 23 is an alpha-aminoisobutyl acid 1 and the carboxyl group of Ala in position 26 is amidated, for example, C0 * NH2 instead of CQ * OH. (Xi) SEQUENCE DESCRIPTION: SEQ ID N0: 3: AP Wing Al. Il «Fhe Thr Xaa Ala Phe Arg Lyß Val Leu AXa Ala Leu
Xaa AXa Arg Lyß AXa Leu Xaa Ala AXa Wing 20 S
(2) INFORMATION FOR SEQ ID N0: 4: (i) CHARACTERISTICS OF SECUENC IA: (A) LENGTH: 25 ami nocides (B) TYPE: ami nocide (OR CONFORMATION OF HEBRA: irrelevant (D) TOPOLOGY: both ( ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (D) OTHER INFORMATION: The amino group of Ala in position 1 is substituted with p-hydroxyphenylpropionyl, Xaa in each of positions 7, 17 and 23 is an acid alpha-aminoisobutyl 1 ico, and the carboxyl group of Ala in position 25 is amidated, for example, C0 * NH2 instead of CO * OH. (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: AXa? ßp AXa lie Phé Thr Xaa Ala Tyr Arg Lyß Val Leu Ala Ala Leu e 5 «V" Xae Ala Arg Lyß Ala Leu Xaa Ala Ala 20 25
(2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 amino acids < B) TYPE: amino acid (C) FABRIC CONFORMATION: irrelevant (D > TOPOLOGY: both (ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (D) OTHER INFORMATION: The amino group of Ala in position 1 it is substituted with p-hydroxyphenylpropionyl, Xaa at each of positions 7, 17 and 23 is an alpha-a inoisobutyl acid, and the carbalayl group of Ala at position 25 is amidated, for example, C0 * NH2 ( CH2) 3CH3 instead of C0 * 0H. (Xi) SEQUENCE DESCRIPTION: SEQ ID N0: 5: Ala Aep Ala He Phe Thr Xaa Ala Tyr Arg Lys val Leu Ala Ala Leu 2 5 10 »Xaa AXa Arg Lyß AXa Leu Xaa Ala Ala 20 25
(2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 ami nocides (B) TI PO: am i nocido (V.) FABRIC CONFORMATION: irrelevant (D) TOPOLOGY : both (ii) TYPE OF MOLECULE: protein (i) CHARACTERISTICS: (D) OTHER INFORMATION: The amino group of Ala in position 1 is substituted with p-hydroxy feni Iprapioni lo; Xaa in each of positions 7, 17 and 23 is an alpha-aminoisabutyl 1 ico acid; and the carboxyl group of Ala in the 24-position is amidated, for example, C0 * NH2 instead of CD * 0H. (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 6: Ala Aßp Ala He Phe Thr Xaa Ala Tyr Arg Lyß Val Leu Ala Ala Leu X 5 10 15 Xaa Ala Arg Lys Ala Leu Xaa Ala 20
(2) INFORMATION FOR SEQ ID N0: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 23 amino acids (B) TYPE: amino acid (C) FABRIC CONFORMATION: irrelevant (D) TOPOLOGY: both di) TYPE OF MOLECULE : protein (ix) CHARACTERISTICS: (D) OTHER INFORMATION: The amino group of Ala in position 1 is substituted with p-hydroxyphenylpropionyl; Xaa in each of positions 7, and 17 is an acid to fa-ami noi sobut í 1 i co; and the carboxyl group of Ala in position 23 is knotted, for example, C0 * NH2 instead of CO * OH. (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 7: Ala Aap Ala? e Phe Thr Xaa Wing Tyr Arg Lyß Val Leu Wing Aia Leu 1 5 10 15 Xaa Wing Arg Lyß Wing Leu Wing 20 (2) INFORMATION FOR SEQ ID N0: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 amino acids (B) TYPE: amino acid (C) FABRIC CONFORMATION: irrelevant (D) TOPOLOGY: both (ii) TYPE OF MOLECULE: protein (ix) CHARACTERISTICS: (D) OTHER INFORMATION: The amino group of Ala in position 1 is found substituted with p-hydroxyphenylpropionyl; Xaa in each of positions 7, 17 and 23 is an alpha-aminoisobutyl-1-yl acid; Xaa in position 26 is Nle; and the carboxyl group of Ala in position 27 is amidated, for example,
C0 * NH2 instead of C0 * 0H. (xi) SEQUENCE DESCRIPTION: SEQ ID N0: 8:
Ala Aßp Ala He Phe Thr Xaa Ala Tyr Arg Lyß Val Leu Ala Ala Leu 1 5 10 15 Xaa Ala Arg Lyß Ala Leu Xaa Ala Ala Xaa Ala 20 2S
Claims (22)
1. A peptide of the formula R1 XA1-A2-Aβ -Ala-Ile-I'h -Thr- Xl0-Ar9-A12"V l- eu- Xl5-16-Leu-A1ß-AXa-rg-A2r 22-Lu-A24-A25-A2rA27-A28-ll3 wherein Al is the D or L isomer of an amino acid selected from the group consisting of Tyr and His, or is 1 i mi; A2 is Aib, or else the D or L isomer of an amino acid selected from the group consisting of Ala, N-Me-Ala, And Arg; A8 is Ala, Aib, or Gly; A9 is Ala, Aib, or Gly; A 10 is Phe or pX-Phe where X is OH, CH 3 or a halogen A 12 is Lys or Nép i lon-X-Lys where X is C 1 -C 6 alkyl, C 1 -C 6 acyl, C 1 -C 6 hydroxyalkyl, or hydro? iacyl C2- C6; A15 is Ala, Aib, or Gly; A16 is Ala, Aib, or Gly; A18 is Ala, Aib, or Gly; A21 is Lys or Népsi lon-X-Lys where X is C 1 -C 6 alkyl, C 1 -C 6 acyl, C 1 -C 6 hydroalkyl, or C 2 -C 6 hydroskyl; A 2 is Ala, Aib, Gly, Leu, He, Val, Nle, Nva, or Abu; A24 is Ala, Aib, Gaba, Gly or His; A25 is Ala, Aib, Gaba, Gly, His, or else it is deleted; A26 is Ala, Aib, Gaba, Gly, His, or is deleted; A27 is Ala, Aib, Gly, Leu, Lie, Val, Nle, Nva, Abu, Gaba, Beta-Ala, Ava, His, or else it is deleted; A28 is Aib, the D isomer or either L of Ala, Gaba, His, or is deleted; each of R1 and R2 is independently H, Cl-C12 alkyl, C7-C20 phenylalkyl, C11-C20 naphthyl, C1-C12 hydraxyalkyl, C7-C20 hydroquinolyl, C11-C20 hydroxynaphthalalkyl , or C0E1, where El is C1-C12 alkyl, C7-C20 phenylalkyl, C11-C20 naphthyl, C1-C12 hydroxyalkyl, C7-C20 hydroxy phenylalkyl, or C11-C20 hydroxynaphtylalkyl; and R3 is OH, NH2, C1-C12 alkoxy or NH "Y-CH2-Z where Y is a portion of C1-C12 hydrocarbon and Z is H, OH, C02H, or C0NH2; or a pharmaceutically acceptable salt thereof.
2. A peptide of claim 1, wherein A25 is Ala, A26 is Ala, A27 is Ala, Aib, Leu, He, Val, Nle, Nva, Gaba, or Abu, and A28 is Ala.
3. A peptide of claim 2, wherein A8 is Ala or Aib, A9 is Ala, A10 is Phe or Tyr, A12 is Lys, A15 is Ala, A16 is Ala, A18 is Al3 or A b, A21 is Lys , A22 is Ala, A24 is Ala or Ajb, and A27 is Ala, Leu, Gaba, or Nle.
4. A peptide of claim 3, wherein A8 is Aib, A18 is Aib, and A24 is Aib.
5. A peptide of claim 4, wherein Al is Tyr, and A2 is D-Ala or L-Ala.
6. A peptide of claim 4, wherein Al is removed, A2 is D-Ala, or L-Ala, Rl is H, and R2 is C0E1.
7. A peptide of claim 3, wherein R3 is NH-Y-CH2-Z.
8. A peptide of claim 1, wherein A28 is removed.
9. A peptide of claim 8, wherein A25 is Ala, A26 is Ala, and A27 is Ala, Aib, Leu, Lie, Val, Nle, Nva, Gaba, or Abu.
10. A peptide of claim 9, wherein A8 is Ala or Aib, A9 is Ala, A10 is Phe or Tyr, A12 is Lys, A15 is Ala, A16 is Ala, A18 is Ala or Aib, A21 is Lys , A22 is Ala, A24 is Ala or Aib, and A27 is Ala, Leu, Gaba, a Nle.
11. A peptide of the rei indication 10, where A8 is Aib, A18 is Aib, and A24 is Aib.
12. A peptide of claim 11 wherein Al is Tyr, and A2 .8 is D-Ala to good L-Ala.
13. A peptide of claim 11, wherein Al is removed, A2 is D-Ala, or L-Ala, Rl is H, and R2 is C0E1.
14. A peptide of claim 10, wherein P3 is NH Y CH2 Z.
15. A peptide of claim 1, wherein A27 is removed and A28 is removed.
16. A peptide of claim 15, wherein A25 is Ala, and A26 is Ala.
17. A peptide of claim 16, wherein A8 is Ala or Aib, A9 is Ala, A10 is Phe or Tyr, A12 is Lys, A15 is Ala, A16 is Ala, AIS is Ala or Aib, A21 is Lys , A22 is Ala, and A24 is Ala or Aib.
18. A peptide of claim 17, wherein A8 is Aib, A18 is Aib, and A24 is Aib.
19. A peptide of the rei indication 18, where Al is Tyr, and A2 is D-Ala or L-Ala.
20. A peptide of claim 18, wherein Al is removed, A2 is D-Ala or L-Ala, Rl is H, and R2 is C0E1.
21. A peptide of claim 17, wherein R3 is NH-Y-CH2-Z.
22. A peptide of claim 1 of the formula: H \ Tyr-D-Ala-Aβp-Ala-Ilβ-Phe-Thr-Aib-Ala-Tyr-Axg-Lyß-Val-H fceu-Ala-Ala-Leu-Aib-Ala-Ar? - yfl-Ala- Lßu-Aib-Ala-Ala-H \ Tyr-D-Ala-Aβp-Ala-Ile-Phe-Thr-Aib-Ala-Tyr-Arg-Lyß-Val-B Lßu-Ala-Ala-Lßu-Aib-Ala -Arg-Lyß-Ala-Leu-Aib-Ala-Ala-mKCBjJjCHj H \ Tyr-D-Ala-ABp-Ala-21e-Phe-Thr-? Ib-Ala-tyr-Arg-Lyß-Val- / H Lßu -Ala-Ala-Leu-Aib-Ala-Arg-Lyß-Ala-Leu-Aib-Ala-Ala-Ala-Niíj I OH \ Tyr-D-Ala-Asp-Ala-Ile-Ph * -Thr-? Ib-Ala-Tyr-Arg-Lya-Val- / K Leu-Ala-Ala-Leu-Aib-A a-Arg- Lyß-Ala-Leu-Aib-Ala-Ala-Leu-NSj H D-Ala-Aap-Ala-lle-Phe-Thr-Aib-Ala-tyr-Arg-Lyß * Val-I-eu * "u Hpp 'Ala-Ala-Leu * Aib-Ala-Arg-Lyß-Ala-Leu-Aib-Ala-Ala-Lßu-KH2 B ^ Tyr-D-Al» -A8p-Ala-Ha-Phe-Thx- A-b-Ala-Tyr-Arg-Lyß-Vai / B Lß «-Ala-Aia-Lßu-Ali» -Ala-Arg-Ly * -Ala-Lßn -Ai> -A? A-Ala- I? le-Ala-m 0 8 ^ yy ^ -Oj ß-Aß ^ Ala-Iie-Phe-T-rix-Ala-AXa-Tyr-Arg-Lyß-VßX- t »/ Leu-Ala-Ala-Leu-Ala-Ala-Arg- Lyß-Ala-Lßni-Ala-Ala-Ala-Ala-Ala-NHj Tyx-D-A a-Aßp-Ala-? Le-Phe-Thr-Alb-Al a-Tyr-Arg-Lyß-Vßl- / H gi ^ u-Ale-Ala-Leu-Aib-Ala-Arg-Lyß-Ala-Lßu-Alb-Ala-Ala-HBj to Tyr-D-Ala-Aβp-AXa-lXe-Phß-Thr-AU > -Ala-Tyr-Arg-Lyß-Val- / H Lau-Ala-Ala-Lßu-Aib-Ala-Arg-LyB-AlA-Lßu-Ala-Ala-Ala-Ala-NHj B? La-Aßp-Ala-Ilß-Phe-Thr-AI.b-Ala-Tyr-Arg-Lyß-Val-Leu- / Hpp AIA-Ala-Leu-Aib-Ala-Arg-LyB-Ala-Leu Aib-Ala-Ala-Hle-Ala-HK2 (SEO ID MOiß), H Tyr-D-Ala-Aβ? -Ala-Ile-Phe-Thr-Aib »AXa-Tyr-Arg-Lyß-val- / H Leu-? La-AXa-Leu-Aib-Ala-Arg-Lyß-AXa -Leu-Aü-Ala-Ala-Cabß-NH- H Ala-ABp-Ala-Ile-Phe-Thr-Aβ-Ala-Tyr-Arg-Lya-vai-Lßu-Ala- / Hpp? Ia-Leu-ib-Ala-Arg-Lyß-Ala-Leu -A - b-Ala-Ala-catoa - JH2 (SSQ XD HOl l), H Tyr-D-Ala-ABp-Ala-IXe-Phe-Thr-Aib-Ala-Tyr-Arg-Lyß-Val-Lßu- / B Ala-Ala-Leu-Aib-Ala-Arg-LyB-A a- Lßu-Aib-A a-Alß-Lßu-Ala-MHj B Ala-Aap-Al aI le-Phe-Thr-Ai -Ala-Tyr-Arg-LyB-Va 1-Leu-Ala- / Bpp Ala-Leu-Aib-Ala-Arg-Lya-Ala-Leu-Aib- Ala-Ala-Ala-MBj. { SEQ ID N0: 2), R \ Al a-Aa? -Ala-I le-Phe-Thr-Aib-Ale-Phe-Arg-Ly 8 -Val -Leu-Al a- BPP. . Ala-L * u-Aib-Ala-Arg-LyB-Ala-Leu-AJ.b-Ala-AXa-Ala -ffl2. { SJSQ ID «0: 3), B \ Ala-Aßp-Ala-lle-Phe-Thr-Aib-Ala-Tyr-Arg-Lyß-Val-Lßu-AIa- H p Ala-Leu-Aib-Ala-Arg- LyB-Ala-Leu-Ai.b'-Ala-Ala-HH, (SEQ 10 NO? 4), To a-Aßp-Ala-Xle-Phe-Thr-α ib-Ala-Tyr-Arg-lyß-Val-Lßu-Ala-Hpp Ala-Leu-Alb-Ala-Arg-Lyß-Ala-Lßu-Aib-Ala -Ala-MH (CH2) JCHJ (SEQ ID NO), B Al a-Aap-AX aI lß-Phe-Thr-Aib-AX a-Tyr-Axg-Ly s-Val-Lßu-Ala-Hpp Ala-Leu-Aib-Ala-Arg-Lyß-Ala-Lau-AIB -Ala-NHj (CH2) jCHj (SEQ 10 NO: 6), Tyr-D-Ala-Aa? -Al »-Il * -Phß-Thr-Aib-Aia-Tyr-Arg-Ly» -Val- Leu-Ala-Ala-Leu-Aib-Ala-Arg-Lya-Ala- Leu-Al a-Ala-Ala-HH2 (CHj) jCHj Tyr-D-Ala-ABp-Ala-Ile-Phe-Thr-Alb-Ala-Tyr-Arg-Lyß-Val-Le-Ala-Ala-Leu-Aib-Ala-Arg-Lyß-Ala-Lßu-Ala Ala-Ala-CB2 (CB2 > éCH3 Tyr-D-Ala-Aßp-Ala-Xle-Phe-Thr-Alb-Ala-Tyr-Arg-Lyß-Val-Lßu-Ala-Ala-Leu-AiJb-Ala-Arg-LyB-Ala-Leu-Ala Ala-BH2 Tyr-DA a-Aßp-Ala-Ile-Phe-Thr-Ai-b-Ala-Tyr-Arg-Lyß-val-Leu-Ala-Ala-Leu-Aib-Ala-Arg-Lyß-Ala-Leu-Ala -HB-, B \ Ala-Aap-Ala-lle-Phe-Thr-Aib-Ala-Tyr-Arg-LyB-Val-Lau-Ala-Hpp Ala-Lßu-Aib-Ala-Arg-Lyfl-Ala-Lßu -Ala-MH2 (SEQ ID NO: 7), H \ Tyr-D-Ala-Aßp-Ala-Ile-Phe-Thr-Aib-Ala-Tyr-Arg »Lyß-Val» H Leu-Ala-Ala-Leu-Aib-Ala-Arg-Lyß-Ala-Leu -Ala-Ala-Ala-Caba- B, (A? Alogo # 24) H \ Tyr-D-Ala-Aβp-Ala-Ile-Phe-Thr-Aib-Ala-Phe-Arg-Lyß-Val-Leu Ala-Ala-Leu-Aib-Ala-Arg-Lyß-Ala-Leu-Ala-Ala-Aia-Oaba-NH, (Analog to S) \! Tyr-D-Ala-Aßp-Ala-1 le-Phe-Thr-Aib-Ala-Tyr-Arg-Lyß-Val-Leu- / B Ala-Ala-Lßu-Aib-Ala-Arg-Lyß-Ala-Leu -Ai-b-Alß-Oaba-MB, (Analogue l «26) . A peptide of claim 1 of the formula: B ^ Tyj-D-Ala-Aßp-Ala-lle-Phe-Thr-Ala-Ala-Tyr-Arg-Lyi-Val- / H Leu-AXa-Ala-Leu-Aia-Ala-Arg-Lyß-Ala Leu-Ala-A a-Ala-Ala-iraj, B ^ Tyr-D-Ala-Aßp-Ala-I le-Phe-Thr-Ala-Ala-Tyr-Arg-Lyß-Val- / "ßu-Ala-A a-Leu-Ala-Alß'Arg-Lyß- Ala-Lßu-Ala-Ala-Ala-HBj B ^ Tyr-e.Ala-Aap-Ala-llß ~ Phe-Thr-Atb-Ala-Tyr-Arg-LyB-Val- / H i? U-Ala-Ala-Lßu-Aib-Ala-Arg-LyB- Ala-Leu-Aib-Ala-Ala? a-Al * - !! ^ K \ Tyr-D-Ala-Aßp-? la-I le-Phe-Thr-Ai-b-AlA-Tyr-Arg-Lyß-Val- / H Leu-Ala-Ala -Lßu-Aib-M a-Arg-Lyß-Ala-Leu-Aib-Ala-Ala-Gaba-HH (CH2) 2CH3 B Tyr-D-Ala-Aßp'Ala-lle-Phe-Thr-Aib-Ala-Tyr-Arg-LyB-Val- / B Leu-Ala-Ala-Leu-Aib-Ala-Ar? -Lya-Ala- Lßu-Aib-Ala-Ala-Gaba-NH (CH-.) 3CHj
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42198795A | 1995-04-14 | 1995-04-14 | |
| US241987 | 1995-04-14 | ||
| US52433795A | 1995-09-06 | 1995-09-06 | |
| US524337 | 1995-09-06 | ||
| PCT/US1996/004582 WO1996032126A1 (en) | 1995-04-14 | 1996-04-03 | Analogs of growth hormone-releasing factor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9707904A MX9707904A (en) | 1997-11-29 |
| MXPA97007904A true MXPA97007904A (en) | 1998-07-03 |
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