Somatostatin agonists

Abstract

Claimed are a series of somatostatin agonists typically characterized by alkylation of the amide nitrogen, and uses thereof. Examples of claimed compounds are those according to formula (I), A1-cyclo{Cys-A2-D-Trp-A3-A4-Cys}-A5-Y1,  (I) wherein: A1 is an optionally substituted D- or L-aromatic α-amino acid or optionally substituted D- or L-cyclo(C3-6)alkylalanine; A2 is an optionally substituted aromatic α-amino acid or optionally substituted cyclo(C3-6)alkylalanine; A3 is Lys or Orn; A4 is β-Hydroxyvaline, Ser, hSer, or Thr; A5 is β-Hydroxyvaline, Ser, hSer, or Thr; and Y1 is OH, NH2 or NHR1, where R1 is (C1-6)alkyl; wherein each said optionally substituted aromatic α-amino acid and each said optionally substituted cyclo(C3-6)alkylalanine is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NO2, OH, CN, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)alkoxy, Bzl, O-Bzl, and NR9R10, where R9 and R10 each is independently H or (C1-6) alkyl; and wherein the amine nitrogen of each peptide bond and the amino group of A1 of formula (I) is optionally substituted with a methyl group, provided that there is at least one said methyl group; and further provided that said compound is not D-Phe-cyclo{Cys-Phe-D-Trp-Lys-(N-Me-Thr)-Cys}-Thr-NH2; or a pharmaceutically acceptable salt thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation application of pending U.S. Ser. No. 10 / 474,248, filed Apr. 26, 2004, which is a United States national filing under 35 U.S.C. §371 of international (PCT) application No. PCT / US02 / 10882, filed Apr. 8, 2002, designating the United States, and claiming priority to U.S. provisional application No. 60 / 282,526, filed Apr. 9, 2001.BACKGROUND OF THE INVENTION [0002] Somatostatin (SRIF), a tetradecapeptide discovered by Brazeau et al., has been shown to have potent inhibitory effects on various secretory processes in tissues such as pituitary, pancreas and gastrointestinal tract. SRIF also acts as a neuromodulator in the central nervous system. These biological effects of SRIF, all inhibitory in nature, are elicited through a series of G protein coupled receptors, of which five different subtypes have been characterized (SSTR-1 to SSTR-5). These five subtypes have similar affinities for the endogenous SRIF lig...

AI Technical Summary

Benefits of technology

The N-methylated peptide analogs demonstrate improved binding affinity and specificity for somatostatin receptor subtypes, reducing side effects and enhancing therapeutic efficacy across a range of diseases and conditions.

Problems solved by technology

One unintended consequence of such structural simplification, carried out before the discovery of multiple receptor subtypes, was the loss of broad spectrum binding affinity.

Thus, the many basic biological studies with this type of analogue failed to detect effects mediated by all but one of the SRIF receptor subtypes.

Only a few N-methyl amino acids are commercially available and their synthesis is tedious.

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