LHRH-II PEPTIDE ANALOGS
First Claim
Patent Images
1. A peptide of the formula
X1-X2-X3-X4-X5-X6-X2-X8-X9-X10,wherein:
- X1 is an optional component which, when present, is selected from the group consisting of Arg, His, pGlu, Sar, Dnal2, Ac-Amfe4, Ac-Dnal2, Dtpi, Damfe4, Bip, Dbpa4, Tpi, Mogly, Ampha4, Dnal1, Qua3, Thy, Atdc2, Dtyr, Apsp, Hpgly, Datdc2 and Ahgly;
X2 is selected from the group consisting of Arg, His, Gufe4, Damfe4, Ampg4, Darg and Ampa4;
X3 is selected from the group consisting of Trp, Arg, Phe, Nal2, Nal1 and Amfe4;
X4 is selected from the group consisting of Ser, Met, Asn, Amfe4 and Dap;
X5 is selected from the group consisting of His, Arg, Orn and Fur3ala;
X6 is selected from the group consisting of Arg and Darg;
X7 is Trp;
X8 is selected from the group consisting of Bpa4, Tyr and Nal2;
X9 is selected from the group consisting of Pro, Am2prd, Thz, Hypt4, Ampc4, Ampt4, Pip, Flp4 and Aze;
or X8 and X9 together can form a dipeptide isostere X8-Ψ
(CH2N)—
X9; and
X10 is an optional component which, when present, is selected from the group consisting of azaGly-NH2, Gly-Arg-NH2, Gly-Gln-NH2, Da15o3t, Gua, Ap, Az34m3buo-NH2, Pheo1, Mo2abn, A1gua5o3pt and Az23m2po-NH2;
with the proviso that the peptide is not pGlu-His-Trp-Ser-His-Darg-Trp-Tyr-Pro-azaGly-NH2 (SEQ ID NO;
199).
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Abstract
The invention is directed to analogs of LHRH-II and, more generally, to analogs of the LHRH family in which modifications have been made that confer enhanced binding affinity for LHRH receptors and/or improved metabolic stability.
The invention is further directed to methods of targeted therapy and targeted imaging in patients with sex-hormone-related cancers or other LHRH-mediated diseases.
14 Citations
33 Claims
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1. A peptide of the formula
X1-X2-X3-X4-X5-X6-X2-X8-X9-X10,wherein: -
X1 is an optional component which, when present, is selected from the group consisting of Arg, His, pGlu, Sar, Dnal2, Ac-Amfe4, Ac-Dnal2, Dtpi, Damfe4, Bip, Dbpa4, Tpi, Mogly, Ampha4, Dnal1, Qua3, Thy, Atdc2, Dtyr, Apsp, Hpgly, Datdc2 and Ahgly; X2 is selected from the group consisting of Arg, His, Gufe4, Damfe4, Ampg4, Darg and Ampa4; X3 is selected from the group consisting of Trp, Arg, Phe, Nal2, Nal1 and Amfe4; X4 is selected from the group consisting of Ser, Met, Asn, Amfe4 and Dap; X5 is selected from the group consisting of His, Arg, Orn and Fur3ala; X6 is selected from the group consisting of Arg and Darg; X7 is Trp; X8 is selected from the group consisting of Bpa4, Tyr and Nal2; X9 is selected from the group consisting of Pro, Am2prd, Thz, Hypt4, Ampc4, Ampt4, Pip, Flp4 and Aze; or X8 and X9 together can form a dipeptide isostere X8-Ψ
(CH2N)—
X9; andX10 is an optional component which, when present, is selected from the group consisting of azaGly-NH2, Gly-Arg-NH2, Gly-Gln-NH2, Da15o3t, Gua, Ap, Az34m3buo-NH2, Pheo1, Mo2abn, A1gua5o3pt and Az23m2po-NH2; with the proviso that the peptide is not pGlu-His-Trp-Ser-His-Darg-Trp-Tyr-Pro-azaGly-NH2 (SEQ ID NO;
199). - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)
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-
16. A peptide selected from the group consisting of BRU-3103 (SEQ ID NO:
- 8), -3042 (SEQ ID NO;
9), -3102 (SEQ ID NO;
8), -2991 (SEQ ID NO;
8), -3045 (SEQ ID NO;
8), -3080 (SEQ ID NO;
8), -3044 (SEQ ID NO;
8), -3039 (SEQ ID NO;
8), -3043 (SEQ ID NO;
8), -3117 (SEQ ID NO;
10), -3041 (SEQ ID NO;
8), -3085 (SEQ ID NO;
8), -2992 (SEQ ID NO;
11), -2441 (SEQ ID NO;
12), -2734 (SEQ ID NO;
13), -3007 (SEQ ID NO;
8), -2439 (SEQ ID NO;
14), -2839 (SEQ ID NO;
15), -2803 (SEQ ID NO;
16), -2821 (SEQ ID NO;
17), -2822 (SEQ ID NO;
18), -3100 (SEQ ID NO;
19), -3115 (SEQ ID NO;
20), -3072 (SEQ ID NO;
21), -2964 (SEQ ID NO;
22), -3105 (SEQ ID NO;
23), -2968 (SEQ ID NO;
24), -2969 (SEQ ID NO;
25), -3068 (SEQ ID NO;
26), -2959 (SEQ ID NO;
27), -3104 (SEQ ID NO;
28), -3111 (SEQ ID NO;
29), -2757 (SEQ ID NO;
30), -3058 (SEQ ID NO;
31), -2956 (SEQ ID NO;
32), -2952 (SEQ ID NO;
33), -2963 (SEQ ID NO;
34), -3070 (SEQ ID NO;
35), -3095 (SEQ ID NO;
36), -3081 (SEQ ID NO;
37), -3031 (SEQ ID NO;
38), -3050 (SEQ ID NO;
39), -3071 (SEQ ID NO;
40), -3053 (SEQ ID NO;
41), -3062 (SEQ ID NO;
42), -2813 (SEQ ID NO;
43), -2997 (SEQ ID NO;
44), -2796 (SEQ ID NO;
45), -3060 (SEQ ID NO;
46), -2961 (SEQ ID NO;
47), -2996 (SEQ ID NO;
48), -3094 (SEQ ID NO;
49), -2811 (SEQ ID NO;
50), -2869 (SEQ ID NO;
51), -3049 (SEQ ID NO;
52), -3027 (SEQ ID NO;
53), -3096 (SEQ ID NO;
54), -2993 (SEQ ID NO;
55), -3057 (SEQ ID NO;
56), -3069 (SEQ ID NO;
57), -3107 (SEQ ID NO;
58), -3055 (SEQ ID NO;
59), -2960 (SEQ ID NO;
60), -2984 (SEQ ID NO;
24), -2955 (SEQ ID NO;
61), -2995 (SEQ ID NO;
62), -3059 (SEQ ID NO;
63), -3098 (SEQ ID NO;
64), -3006 (SEQ ID NO;
24), -3054 (SEQ ID NO;
65), -3106 (SEQ ID NO;
66), -2696 (SEQ ID NO;
67), -2967 (SEQ ID NO;
68), -3056 (SEQ ID NO;
69), -3099 (SEQ ID NO;
70), -2797 (SEQ ID NO;
71), -2983 (SEQ ID NO;
24), -3020 (SEQ ID NO;
24), -3097 (SEQ ID NO;
72), -2985 (SEQ ID NO;
24), -2666 (SEQ ID NO;
73), -2962 (SEQ ID NO;
74), -3025 (SEQ ID NO;
75), -3063 (SEQ ID NO;
76), -2971 (SEQ ID NO;
77), -2876 (SEQ ID NO;
78), -3002 (SEQ ID NO;
79), -3021 (SEQ ID NO;
24), -2994 (SEQ ID NO;
80), and -2953 (SEQ ID NO;
81).
- 8), -3042 (SEQ ID NO;
-
19. An LHRH-analog peptide of the formula
X1-X2-X3-Ser-X5-Darg-X7-X8-Pro-azaGlyNH2,wherein: -
X1 is selected from the group consisting of Arg, His, pGlu, Sar, Dnal2, Ac-Amfe4, Ac-Dnal2, Dtpi, Damfe4, Bip, Dbpa4, Tpi, Mogly, Ampha4, Dnal1, Qua3, Thy, Atdc2, Dtyr, Apsp, Hpgly, Datdc2 and Ahgly; X2 is selected from the group consisting of Arg, His, Gufe4, Damfe4, Ampg4, Darg and Ampa4; X3 is selected from the group consisting of Trp and Tyr; X5 is selected from the group consisting of His, Leu and Tyr; X2 is selected from the group consisting of Leu and Trp; and X8 is selected from the group consisting of Bpa4 and Nal2, or the Bpa4 or Nal2 at position 8 can form a dipeptide Ψ
(CH2N) isostere with the Pro at position 9. - View Dependent Claims (20, 21)
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-
22. A metabolically stabilized LHRH-II analog of the formula
X1-X2-Trp-Ser-His-X6-Trp-X8-X9-GlyNH2,wherein X1 is selected from the group consisting of pGlu, Dnal2 and Sar; - X2 is Arg;
X6 is Darg;
X8 is Bpa4; and
X9 is selected from the group consisting of Pro, Am2prd, Thz, Hypt4, Ampc4, Ampt4, Pip, Flp4 and Aze; andwherein when X9 is Pro, it and the Bpa4 at position 8 together form a dipeptide Ψ
(CH2N) isostere. - View Dependent Claims (23)
- X2 is Arg;
Specification