Cyclic octapeptide neuromedin B receptor antagonists

Details Cyclic octapeptide neuromedin B receptor antagonists Cyclic octapeptide neuromedin B receptor antagonists

1994-12-08

1996-10-29

Davenport, Avis M.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Somatostatin ; related peptides

530317, 530328, A61K 3800, C07K 500, C07K 700, C07K 1700

Patent

active

055697410

ABSTRACT:
A cyclic octapeptide of the formula: ##STR1## wherein: A.sup.1 is D-Nal or D-Trp;
A.sup.3 is Phe, F.sub.5 -Phe, or X-Phe wherein X is a halogen, NO.sub.2, CH.sub.3, or OH;
A.sup.5 is --NH--CH(Y)--CO-- wherein Y is (CH.sub.2).sub.m --R.sub.4 --N(R.sub.5)(R.sub.6) or (CH.sub.2).sub.n --R.sub.4 --NH--C(R.sub.7)--N(R.sub.5) (R.sub.6);
A.sup.6 is the D-- or L-- isomer of Thr, Leu, Ile, Nle, Val, and Abu;
A.sup.8 is Nal or Trp;
m is 1, 2, or 3;
n is 1, 2, 3, 4 or 5;
each of R.sub.1 and R.sub.2, independently, is H, E, COE, or COOE wherein E is C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, phenyl, naphthyl, C.sub.7-12 phenylalkyl or alkylphenyl, C.sub.8-12 phenylalkenyl or alkenylphenyl, C.sub.8-12 phenylalkynyl or alkynylphenyl, C.sub.11-20 naphthylalkyl or alkylnaphthyl, C.sub.12-20 naphthylalkenyl or alkenylnaphthyl, or C.sub.12-20 naphthylalkynyl or alkynylnaphthyl, provided that when one of R.sub.1 or R.sub.2 is COE or COOE, the other must be H;
R.sub.4 is C.sub.6 H.sub.4 or absent;
R.sub.7 is .dbd.NR.sub.8, .dbd.S, or .dbd.O; and
each of R.sub.3, R.sub.5, R.sub.6, and R.sub.8, independently, is H or E.

REFERENCES:
patent: 5003011 (1991-03-01), Coy et al.
Smith et al., "Principles of Biochemistry: General Aspects", Seventh Edition, published 1983 by MacGraw-Hill (N.Y.), pp. 32-33 and 617, see entire document.
PCT search report dated 1 Apr. 1996.
Benya et al., "Neuromedin B Receptors Retain Functional Expression when Transfected into BALB 3T3 Fibroblasts: Analysis of Binding, Kinetics, Stoichiometry, . . . ", Molecular Pharmacology, 42:1058-1068, 1992.
Coy et al., "Solid Phase Reductive Alkylation Techniques in Analogue Peptide Bond and Side-Chain Modification", Tetrahedron, 44:835-841, 1988.
Kawai et al., "Effects of Neuromedin B and GRP-10 on Gastrin and Insulin Release from Cultured Tumor Cells of a Malignant Gastrinoma", Endocrinol. Japan. 37 (6), 857-865, 1990.
Ladenheim et al., "Capsaicin Attenuates bombesin-induced Suppression of Food Intake", Am. J. Physiol. 260 (Regulatory Integrative Comp. Physiol. 29): R263-R266, 1991.
Moody et al., "Neuromedin B Binds with High Affinity, Elevates Cytosolic Calcium and Stimulates the Growth of Small-Cell Lung Cancer Cell Lines", The Journal of Pharmacology & Experi. Therapeutics, 263:311-317, 1992.
Orbuch et al., "Discovery of a Novel Class of Neuromedin B Receptor Antagonists, Substituted Somatostatin Analogues", Molecular Pharmacology, 44:841-850, 1993.
Sasaki et al., "Solid-Phase Synthesis and Biological Properties of .psi.[CH.sub.2 NH] Pseudopeptide Analogues of a Highly Potent Somatostatin Octapeptide", J. Med. Chem. 30:1162-1166, 1987.
Wada et al., "cDNA Cloning, Characterization, and Brain Region-Specific Expression of a Neuromedin-B-Preferring Bombesin Receptor", Neuron, 6:421-430, 1991.
Wang et al., "Activation of Neuromedin B-Preferring Bombesin Receptors on Rat Glioblastoma C-6 Cells Increases Cellular CA.sup.2+ and Phosphoinositides", Biochem. J. 286:641-648, 1992.
STN international "Fast Notes" paper.

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