Details for Patent: 5,939,386
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Title: | Chimeric fatty body-pro-GRF (1-29) analogs with increased biological potency |
Abstract: | The present invention relates to chimeric fatty body-pro-GRF analogs with increased biological potency, their application as anabolic agents and in the diagnosis and treatment of growth hormone deficiencies. The chimeric fatty body-pro-GRF analogs include an hydrophobic moiety (tail), and can be prepared, either by anchoring one or several hydrophobic tails to the GRF, or by substituting one or several amino-acids by a pseudomicellar residue in the chemical synthesis of GRF. The GRF analogs of the present invention are biodegradable, non-immunogenic and exhibit an improved anabolic potency with a reduced dosage and prolonged activity. |
Inventor(s): | Ibea; Michel (Montreal, CA), Abribat; Thierry (Montreal, CA), Brazeau; Paul (Montreal, CA) |
Assignee: | Theratechnologies Inc. (Montreal, CA) |
Filing Date: | Aug 23, 1996 |
Application Number: | 08/702,113 |
Claims: | 1. A chimeric fatty body GRF analog with increased biological potency, of the following general formula: wherein, A1 is Tyr or His; A2 is Val or Ala; A8 is Asn or Ser; A15 is Ala or Gly; A18 is Ser or Thr; A24 is Gin or His; A27 is Met, Ile or Nle; A28 is Ser or Asp; R.sub.0 is NH.sub.2 or NH--(CH.sub.2).sub.n --CONH.sub.2, with n=1 to 12; and wherein A1 is N-anchored by a hydrophobic tail of the following general formula I: ##STR5## wherein, G is a carbonyl group; X is a oxygen atom, sulfur atom or an amino group (NH); (W.dbd.Y) represents cis or trans (CH.dbd.CR.sub.5); (W'.dbd.Y') represents cis or trans (CH.dbd.CR.sub.6); Z is an oxygen or a sulfur atom; R.sub.1 R.sub.2 and R.sub.3, independently, are selected from a hydrogen atom, and a linear or branched C.sub.1 -C.sub.6 alkyl group; R.sub.4 is a hydrogen atom; R.sub.5 and R.sub.6, independently, are a hydrogen atom or a linear or branched C.sub.1 -C.sub.4 alkyl group; a is 1; b is 0; c is 0 to 3; d is 0 or 1; e is 0 to 3; f is 0 or 1; g is 0 to 4; h is 0; wherein the sum of d+f=1 or 2 and the sum of a, b, c, d, e, f, g and h is such that the hydrophobic tail of formula I has a linear main chain of between 5 and 7 carbon atoms. 2. The chimeric fatty body GRF analog of claim 1, wherein c is 0. 3. The chimeric fatty body GRF analog of claim 2, wherein R0 is NH2. 4. The chimeric fatty body GRF analog of claim 3 of the formula cisCR3-CH2-CH.dbd.CH--CH2-CO-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-L ys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2 or transCH3-CH2-CH.dbd.CH--CH2-CO-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg -Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH 5. The chimeric fatty body GRF analog of claim 1, wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 =hydrogen atom and the sum c+e+g=2, 3 or 4. 6. The chimeric fatty body GRF analog of claim 1, wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 =hydrogen atom; and the sum c+e+g=3, 4, or 5. 7. The chimeric fatty body GRF analog of claim 3 of the formula transCH.sub.3 --CH.sub.2 --CH.dbd.CH--CH.sub.2 --CO-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-S er-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH.sub.2. 8. A pharmaceutical formulation for inducing growth hormone release which comprises, as an active ingredient, a GRF analog as claimed in claim 1 or 7, in association with a pharmaceutically acceptable carrier, excipient or diluent. 9. A method of increasing the level of growth hormone in a patient which comprises administering to said patient an effective amount of a GRF analog as claimed in claim 1 or 7. 10. A method for the diagnosis of growth hormone deficiencies in patients, which comprises administering to said patient a GRF analog as claimed claim 1 or 7 and measuring the growth hormone response. 11. A method for the treatment of pituitary dwarfism or growth retardation in a patient, which comprises administering to said patient an effective amount of a GRF analog as claimed in claim 1 or 7. 12. A method for the treatment of wound or bone healing in a patient, which comprises administering to said patient an effective amount of a GRF analog as claimed in claim 1 or 7. 13. A method for the treatment of osteoporosis in a patient, which comprises administering to said patient an effective amount of a GRF analog as claimed in claim 1 or 7. 14. A method for improving protein anabolism in human or animal, which comprises administering to said human or animal an effective amount of a GRF analog as claimed in claim 1 or 7. 15. A method for inducing a lipolytic effect in human or animal inflicted with clinical obesity, which comprises administering to said human or animal an effective amount of a GRF analog as claimed in claim 1 or 7. 16. A method for the overall upgrading of somatroph function in human or animal, which comprises administering to said human or animal an effective amount of a GRF analog as claimed in claim 1 or 7. |