Improved cyclic crf agonists

Details Improved cyclic crf agonists Improved cyclic crf agonists

C - Chemistry, Metallurgy

07

K

C07K 14/575 (2006.01) G01N 33/566 (2006.01) G01N 33/68 (2006.01) G01N 33/74 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2207576

Novel cyclic CRF agonist peptides have the amino acid sequence: (cyclo 30- 33)Ac-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-D-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu- Nle-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-R30-Ala-R32-R33-Asn-Arg-Lys-Leu-Nle-Glu- Ile-Ile-NH2 wherein R30 is Glu or Cys; R32 is His or a D-amino acid such as D- His, D-Arg or similar; R33 is Lys, Orn or Cys. The N-terminus may be extended by Ser-Glu-Glu. Lys may be substituted for Arg23, and its side chain connected by a lactam bridge to Glu20 to form a bicyclic peptide. Certain disclosed CRF agonists include: (cyclo 30-33)[Ac-Pro4, D-Phe12, Nle21,38, D-His32, Glu30, Lys33]r/hCRF(4-41), (cyclo 30-33)[Ac-Pro4, D-Phe12, Nle21,38, D-His32, Glu30, Orn33]r/hCRF(4-41), (cyclo 30-33)[Ac-Pro4, D-Phe12, Nle21,38, Cys30,33, D- His32]r/hCRF(4-41), (bicyclo 20-23, 30-33)[Ac-Pro4, D-Phe12, Nle21,38, Lys23,33, Glu30, D-His32]-r/hCRF(4-41), (cyclo 30-33)[Ac-Pro4, D-Phe12, Nle21,38, CML27, Glu30, imBzlD-His32, Lys33]r/hCRF(4-41) and (cyclo 30-33)[Ac- Pro4, D-Phe12, Nle21,38, Glu30, D-Arg32, Lys33]r/hCRF(4-41). Labelled agonists such as (cyclo 30-33)[I125Tyr0, D-Phe12, Nle21,38, Glu30, D-His32, Lys33]r/hCRF and (cyclo 30-33)[I125D-Tyr3, D-Phe12, Nle21,38, Glu30, D-His32, Lys33]r/hCRF(3-41) are useful in screening for more potent agonists.

Nouveaux peptides cycliques agonistes du facteur libérateur de corticotrophine ayant la séquence d'acides aminés suivante: (cyclo 30-33)Ac-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-D-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-R¿30?-Ala-R¿32?-R¿33?-Asn-Arg-Lys-Leu-Nle-Glu-Ile-Ile-NH¿2?, où R¿30? désigne Glu ou Cys, où R¿32? désigne His ou un D-amino-acide tel que D-His, D-Arg ou un élément semblable et où R¿33? désigne Lys, Orn ou Cys. On peut prolonger l'extrémité N-terminale par Ser-Glu-Glu. On peut remplacer Arg?23¿ par Lys et relier sa chaîne latérale à Glu?20¿ par un pont de lactame pour former un peptide bicyclique. On trouve, parmi les agonistes du facteur libérateur de corticotrophine présentés: (cyclo 30-33)[Ac-Pro?4¿, D-Phe?12¿, Nle?21,38¿, D-His?32¿, Glu?30¿, Lys?33¿]r/hCRF(4-41);(cyclo 30-33)[Ac-Pro?4¿, D-Phe?12¿, Nle?21,38¿, D-His?32¿, Glu?30¿, Orn?33¿]r/hCRF(4-41); (cyclo 30-33)[Ac-Pro?4¿, D-Phe?12¿, Nle?21,38¿, Cys?30,33¿, D-His?32¿]r/hCRF(4-41); (bicyclo 20-23, 30-33)[Ac-Pro?4¿, D-Phe?12¿, Nle?21,38¿, Lys?23,33¿, Glu?30¿, D-His?32¿]r/hCRF(4-41); (cyclo 30-33)[Ac-Pro?4¿, D-Phe?12¿, Nle?21,38¿, CML?27¿, Glu?30¿, imBzlD-His?32¿, Lys?33¿]r/hCRF(4-41) et (cyclo 30-33)[Ac-Pro?4¿, D-Phe?12¿, Nle?21,38¿, Glu?30¿, D-Arg?32¿, Lys?33¿]r/hCRF(4-41). Des agonistes marqués tels que (cyclo 30-33)[I?125¿Tyr?0¿, D-Phe?12¿, Nle?21,38¿, Glu?30¿, D-His?32¿, Lys?33¿]r/hCRF et (cyclo 30-33)[I?125¿D-Tyr?3¿, D-Phe?12¿, Nle?21,38¿, Glu?30¿, D-His?32¿, Lys?33¿]r/hCRF(3-41) sont utiles pour la recherche d'agonistes plus puissants.

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