Claims for Patent: 5,861,379

Summary for Patent: 5,861,379

Title:	Chimeric fatty body-pro-GRF 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)
Application Number:	08/702,114
Patent Claims:	1. A chimeric fatty bodyGRF 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; A18 is Ser or Thr A15 is Ala or Gly; A24 is Gln or His; A27 is Met, Ile or Nle; A28 is Ser or Asp; A30 is any amino acid sequence of 1 to 15 residues; R.sub.0 is NH2; wherein A1 is N-anchored by a hydrophobic tail of the following general formula I: ##STR6## 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.CR5); (W'.dbd.Y') represents cis or trans (CH.dbd.CR6); 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.sup.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 to 1; 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 bodyGRF analog of claim 1, wherein c is 0. 3. The chimeric fatty bodyGRF analog of claim 2, wherein A30 is Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu. 4. The chimeric fatty bodyGRF analog of claim 3, wherein R.sub.0 is NH.sub.2. 5. The chimeric fatty bodyGRF analog of claim 4, of the formula cisCH.sub.3 --CH.sub.2 --CH.dbd.CH--CH.sub.2 --CO-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Rsn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-S er-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln- Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH.sub.2 or 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-Gln-Gln-Gly-Glu-Ser-AsH-Gln- Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH.sub.2. 6. The chimeric fatty bodyGRF analog of claim 1, wherein the sum d+f=2; 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. 7. The chimeric fatty bodyGRF 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. 8. The chimeric fatty body GRF analog of claim 4, 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-Gln-Gln-Gly-Glu-Ser-Asn-Gln- Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH.sub.2. 9. A pharmaceutical formulation for inducing growth hormone release which comprises as an active ingredient a GRF analog as claimed in claims 1 or 8, in association with a pharmaceutically acceptable carrier, excipient or diluent. 10. 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 claims 1 or 8. 11. A method for the diagnosis of growth hormone deficiencies in patients, which comprises administering to said patient a GRF analog as claimed in claims 1 or 8 and measuring the growth hormone response. 12. 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 claims 1 or 8. 13. 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 claims 1 or 8. 14. 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 claims 1 or 8. 15. 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 claims 1 or 8. 16. 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 claims 1 or 8. 17. 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 claims 1 or 8.