Improved cyclic crf antagonists

Details Improved cyclic crf antagonists Improved cyclic crf antagonists

C - Chemistry, Metallurgy

07

K

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

Patent

CA 2206059

Novel cyclic CRF antagonist peptides have the amino acid sequence: (cyclo 30- 33)Y-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 Y is Ac, H, Ac- Thr or H-Thr; R30 is Glu or Cys; R32 is His or preferably a basic and/or aromatic D-amino acid such as D-His or D-Arg; R33 is Lys, Orn or Cys. The N- terminus may be extended by Leu or Asp-Leu. CML may be substituted for Leu27, and D-Tyr may be substituted for D-Phe to facilitate labelling. Lys may be substituted for Arg23, and its side chain connected by a lactam bridge to Glu20 to form a bicyclic peptide. Disclosed CRF antagonists include: (cyclo 30- 33)[D-Phe12, Nle21,38, Glu30, Lys33]r/hCRF(12-41); cyclo 30-33)[Ac-Thr11, D- Phe12, Nle21,38, Glu30, Lys33]r/hCRF(11-41); (cyclo 30-33)[D-Phe12, Nle21,38, Cys30-33]r/hCRF(12-41); (bicyclo 20-23, 30-33)[D-Phe12, Nle21,38, Lys23,33, GLu30]-r/hCRF(12-41); (cyclo 30-33)[D-Phe12, Nle21,38, Glu30, D-His32, Lys33]r/hCRF(12-41); (cyclo 30-33)[D-Phe12, Nle21,38, CML27, Glu30, D-His32, Lys33]r/hCRF(12-41) and (cyclo 30-33)[D-Phe12, Nle21,38, Glu30, D-Arg32, Lys33]r/hCRF(12-41). Labelled antagonists such as (cyclo 30-33)[I125D-Tyr12, Nle21,38, Glu30, D-His32, Lys33]r/hCRF(12-41) are useful in drug screening assays.

La présente invention concerne de nouveaux peptides cycliques antagonistes du facteur de corticotropine (CRF) qui présentent la séquence aminoacide suivante: (cyclo 30-33)Y-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 Y est Ac, H, Ac-Thr ou H-Thr; R¿30? est Glu ou Cys; R¿32? est His ou, de préférence, un D-aminoacide basique et/ou aromatique, tel que D-His ou D-Arg; R¿33? est Lys, Orn ou Cys. La terminaison N peut être prolongée par Leu ou Asp-Leu. CML peut être substitué à Leu?27¿, et D-Tyr peut être substitué à D-Phe pour faciliter le marquage. Lys peut être substitué à Arg?23¿ et sa chaîne latérale peut être reliée à Glu?20¿ par un pont de lactame pour former un peptide bicyclique. Les antagonistes du facteur de corticotropine qui sont révélés comprennent: (cyclo 30-33)[D-PhE?12¿, Nle?21,38¿, Glu?30¿, Lys?33¿]r/hCRF(12-41); (cyclo 30-33) [Ac-Thr?11¿, D-Phe?12¿, Nle?21,38¿, Glu?30¿, Lys?33¿]r/hCRF(11-41); (cyclo 30-33)[D-Phe?12¿, Nle?21,38¿, Cys?30-33¿]r/hCRF(12-41); (bicyclo 20-23, 30-33)[D-Phe?12¿, Nle?21,38¿, Lys?23,33¿, GLu?30¿]r/hCRF(12-41); (cyclo 30-33)[D-Phe?12¿, Nle?21,38¿, Glu?30¿, D-His?32¿, Lys?33¿]r/hCRF(12-41); (cyclo 30-33)[D-Phe?12¿, Nle?21,38¿, CML?27¿, Glu?30¿, D-His?32¿, Lys?33¿]r/hCRF(12-41) and (cyclo 30-33)[D-Phe?12¿, Nle?21,38¿, Glu?30¿, D-Arg?32¿,Lys?33¿]r/hCRF(12-41). Des antagonistes marqués, tels que le (cyclo 30-33)[I?125¿D-Tyr?12¿, Nle?21,38¿, Glu?30¿, D-His?32¿, Lys?33¿]r/hCRF(12-41), sont utiles dans les méthodes de criblage de médicaments.

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