ANALOGUES OF NEUROPEPTIDE Y HAVING AT LEAST ONE SYNTHETIC AMINO ACID SUBSTITUTIONThe present invention relates to novel analogues of neuropeptide Y, pharmaceutical compositions containing the same, pharmaceutical formulations containing the same, and method of treating diseases or conditions mediated by neuropeptide Y-receptor binding. More particularly, the present invention relates to novel analogues of neuropeptide Y having at least one unnatural amino acid substitution, such as 4Hyp at position 34, that selectively bind to the neuropeptide Yl receptor subtype compared to the neuropeptide Y2 receptor subtype.A compound according to formula (I) (SEQ DD NO: 2):(R^^-A^A^A^A'-^^-^-^^^10^''^^^13^'^^^^^17^^^^-^0-A21.A22_A23.A24.A25.A26.A27.A28.A29.A30.A31.A32.A33.A34.A35.A36.A37.Rl(I) wherein: A1 is Tyr, (X1 ,X2,X3,X4,X5)Phe, or HN-CH((CH2)n-N(R4R5))-C(O);A2 is Pro, 3Hyp, cis-3Hyp, 4Hyp, or cis-4Hyp;A3 is Ser, Abu, Aib, Ala, Thr, or HN-CH((CH2)n-N(R4R5))-C(O);A4 is Lys, Arg, hArg, Dab, Dap, Orn, or HN-CH((CH2)n-N(R4R5))-C(O);A5 is Pro, 3Hyp, cis-3Hyp, 4Hyp, or cis-4Hyp; A6 is Asp, Aib, Asn, GIn, GIu, or HN-CH((CH2)n-N(R4R5))-C(O);A7 is Asn, Aib, GIn, or HN-CH((CH2)n-N(R4R5))-C(O);A8 is Pro, 3Hyp, cis-3Hyp, 4Hyp, or cis-4Hyp;A9 is GIy, Aib, or HN-CH((CH2)n-N(R4R5))-C(O);A10 is GIu, Aib, Asn, Asp, GIn, or HN-CH((CH2)n-N(R4R5))-C(O); A1 ' is Asp, Aib, Asn, GIn, GIu, or HN-CH((CH2)n-N(R4R5))-C(O);A12 is Ala, Abu, Aib, Nva, VaI, or HN-CH((CH2)n-N(R4R5))-C(O);A13 is Pro, 3Hyp, cis-3Hyp, 4Hyp, or cis-4Hyp;A14 is Ala, Abu, Aib, Nva, VaI, or HN-CH((CH2)n-N(R4R5))-C(O);A15 is GIu, Aib, Asn, Asp, GIn, or HN-CH((CH2)n-N(R4R5))-C(O); A16 is Asp, Aib, Asn, GIn, GIu, or HN-CH((CH2)n-N(R4R5))-C(O);A17 is Met, Ace, Aib, Cha, He, Leu, hLeu, NIe, Nva, Tie, VaI, or HN-CH((CH2)n-N(R4R5))-C(O);A18 is Ala, Abu, Aib, Nva, VaI, or HN-CH((CH2)n-N(R4R5))-C(O);A19 is Arg, hArg, Ape, Dab, Dap, Lys, Orn, or HN-CH((CH2)n-N(R4R5))-C(O); A20 is Tyr, (X1 ,X2,X3,X4,X5)Phe, or HN-CH((CH2)n-N(R4R5))-C(O);A21 is Tyr, (X',X2,X3,X4,X5)Phe, or HN-CH((CH2)n-N(R4R5))-C(O);A22 is Ser, Abu, Aib, Ala, Thr, or HN-CH((CH2)n-N(R4R5))-C(O);A23 is Ala, Abu, Aib, Nva, VaI, or HN-CH((CH2)n-N(R4R5))-C(O);A24 is Leu, Ace, Cha, He, hLeu, NIe, Nva, Tie, VaI, or HN-CH((CH2)n-N(R4R5))- C(O); A25 is Arg, hArg, Dab, Dap, Lys, Om, or HN-CH((CH2)n-N(R4R5))-C(O);A26 is His, 2PaI, 3PaI, 4PaI, or HN-CH((CH2)n-N(R4R5))-C(O);A27 is Tyr, (X1,X2,X3,X4,X5)Phe, or HN-CH((CH2)n-N(R4R5))-C(O);A28 is He, Ace, Cha, Leu, hLeu, NIe, Nva, Tie, VaI, or HN-CH((CH2)n-N(R4R5))- C(O);A29 is Asn, Aib, GIn, or HN-CH((CH2)n-N(R4R5))-C(O);A30 is Leu, Ace, Cha, He, hLeu, NIe, Nva, Tie, VaI, or HN-CH((CH2)n-N(R4R5))-C(O);A31 is He, Ace, Cha, Leu, hLeu, NIe, Nva, Tie, VaI, or HN-CH((CH2)n-N(R4R5))- C(O);A32 is Thr, Aib, Ser, or HN-CH((CH2)n-N(R4R5))-C(O);A33 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2)n-N(R4R5))-C(O);A34 is GIn, Asn, Dhp, 3Hyp, cis-3Hyp, 4Hyp, cis-4Hyp, Inp, Ktp, Nip, Oic, hPro, Tic, or HN-CH((CH2)n-N(R4R5))-C(O); A35 is Arg, Aic, Ape, hArg, Dab, Dap, Lys, Orn, NH2Phe, NH2CH2Phe, orHN-CH((CH2)n-N(R4R5))-C(O);A36 is Tyr, Aic, (X1,X2,X3,X4,X5)Phe, or HN-CH((CH2)n-N(R4R5))-C(O);A37 is HN-CH((CH2)n-N(R4R5))-C(O) or deleted;R1 is OH, NH2, (Ci-30)alkoxy, or NH-X6-CH2-X7, wherein X6 is a (C1-40)alkyl or (C2-40)alkenyl, and wherein X7 is H, OH, CO2H, or C(O)-NH2;R2 and R3 each is, independently for each occurrence, selected from the group consisting of H, (Ci-30)alkyl, (C1-3o)heteroalkyl, (C1-30)acyl, (C2-30)alkenyl, (C2-30)alkynyl, aryl(C1-30)alkyl, aryl(Ci-3o)acyl, substituted (C1-3o)alkyl, substituted (Ci-30)heteroalkyl, substituted (C2-3o)acyl, substituted (C2-3o)alkenyl, substituted (C2-3o)alkynyl, substituted aryl(C1-3o)alkyl, and substituted aryl(C1-3o)acyl; provided that when R2 is (C1-3o)acyl, aryl(C1-3o)acyl, substituted (C2-30)acyl, or substituted aryl(C1-30)acyl, R3 is H, (C1-3o)alkyl, (Ci-3o)heteroalkyl, (C2-3o)alkenyl, (C2-3o)alkynyl, aryl(Ci-3o)alkyl, substituted (C1-3o)alkyl, substituted (C1-3o)heteroalkyl, substituted (C2-30)alkenyl, substituted (C2-3o)alkynyl, or substituted aryl(C1-3o)alkyl; R4 and R5 each is, independently for each occurrence, H, (Ci-40)alkyl, (Ci-4o)heteroalkyl, (Ci-4o)acyl, (C2-4o)alkenyl, (C2-4o)alkynyl, aryl(C1-4o)alkyl, aryl(C1-4o)acyl, substituted (d-4o)alkyl, substituted (CMo)heteroalkyl, substituted (Ci-40)acyl, substituted (C2-4θ)alkenyl, substituted (C2-4o)alkynyl, substituted aryl(Ci-4o)alkyl, substituted aryl(C1-4o)acyl, (Ci-4o)alkylsulfonyl, or C(NH)-NH2, wherein when R4 is (Ci^acyl, aryl(Ci-4o)acyl, substituted (C1-40)ECyI, substituted aryl(Ci-4o)acyl, (C1-40)alkylsulfonyl, or C(NH)-NH2, then R5 is H or (CrC4o)alkyl, (C1-40)heteroalkyl, (C2-40)alkenyl, (C2-40)alkynyl, aryl(C1-4o)alkyl, substituted (Ci-4o)alkyl, substituted (CM0)heteroalkyl, substituted (C2-4o)alkenyl, substituted (C2-4o)alkynyl, or substituted aryl(d _40)alkyl; n is, independently for each occurrence, 1, 2, 3, 4, or 5;X1, X2, X3, X4, and X5 each is, independently for each occurrence, H, F, Cl, Br, I, (Ci- 10)alkyl, substituted (C1-10)alkyl, aryl, substituted aryl, OH, CH2NH2, NH2, NO2, or CN; and provided that the compound contains at least one substitution with an unnatural amino acid; or a pharmaceutically acceptable salt thereof.
하나 이상의 합성 아미노산 치환을 가지는 뉴로펩타이드 Ｙ 유사체본 발명은 신규한 뉴로펩타이드 Y 유사체, 이를 포함하는 약학 조성물, 이를 포함하는 약학 제형 및 뉴로펩타이드 Y-수용체 결합에 의해 매개되는 질환 또는 증상의 치료 방법에 관한 것이다. 보다 상세하게는, 본 발명은 본원에서 정의된 바와 같이 34번 위치에 4Hyp 등의 하나 이상의 비천연 아미노산 치환을 가지고 있으며, 뉴로펩타이드 Y2 수용체 서브타입과 비교하여 뉴로펩타이드 Y1 수용체 서브타입에 선택적으로 결합하는, 신규한 뉴로펩타이드 Y 유사체에 관한 것이다.식 (I)로 표시되는 화합물 (서열번호 2) 또는 그의 약제학적으로 허용가능한 염:(R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-R1 (I)상기 식 (I)에서,A1은 Tyr, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A2는 Pro, 3Hyp, cis-3Hyp, 4Hyp, 또는 cis-4Hyp이고;A3는 Ser, Abu, Aib, Ala, Thr, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A4는 Lys, Arg, hArg, Dab, Dap, Orn, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A5는 Pro, 3Hyp, cis-3Hyp, 4Hyp, 또는 cis-4Hyp이고;A6는 Asp, Aib, Asn, Gln, Glu, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A7은 Asn, Aib, Gln, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A8은 Pro, 3Hyp, cis-3Hyp, 4Hyp, 또는 cis-4Hyp이고;A9은 Gly, Aib, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A10은 Glu, Aib, Asn, Asp, Gln, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A11은 Asp, Aib, Asn, Gln, Glu, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A12은 Ala, Abu, Aib, Nva, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A13은 Pro, 3Hyp, cis-3Hyp, 4Hyp, 또는 cis-4Hyp이고;A14은 Ala, Abu, Aib, Nva, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A15은 Glu, Aib, Asn, Asp, Gln, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A16은 Asp, Aib, Asn, Gln, Glu, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A17은 Met, Acc, Aib, Cha, Ile, Leu, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A18은 Ala, Abu, Aib, Nva, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A19은 Arg, hArg, Apc, Dab, Dap, Lys, Orn, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A20은 Tyr, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A21은 Tyr, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A22는 Ser, Abu, Aib, Ala, Thr, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A23는 Ala, Abu, Aib, Nva, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A24는 Leu, Acc, Cha, Ile, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A25는 Arg, hArg, Dab, Dap, Lys, Orn, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A26는 His, 2Pal, 3Pal, 4Pal, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A27은 Tyr, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A28은 Ile, Acc, Cha, Leu, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A29은 Asn, Aib, Gln, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A30는 Leu, Acc, Cha, Ile, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A31은 Ile, Acc, Cha, Leu, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A32는 Thr, Aib, Ser, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A33는 Arg, hArg, Dab, Dap, Lys, Orn, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A34는 Gln, Asn, Dhp, 3Hyp, cis-3Hyp, 4Hyp, cis-4Hyp, Inp, Ktp, Nip, Oic, hPro, Tic, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A35는 Arg, Aic, Apc, hArg, Dab, Dap, Lys, Orn, NH2Phe, NH2CH2Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A36는 Tyr, Aic, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A37은 HN-CH((CH2)n-N(R4R5))-C(O) 또는 생략되고;R1은 OH, NH2, (C1-30)알콕시, 또는 NH-X6-CH2-X7이되, 상기 X6는 (C1-40)알킬 또는 (C2-40)알케닐이고, 상기 X7은 H, OH, CO2H, 또는 C(O)-NH2이고;R2 및 R3는 각각 각 경우에 독립적으로, H, (C1-30)알킬, (C1-30)헤테로알킬, (C1-30)아실, (C2-30)알케닐, (C2-30)알키닐, 아릴(C1-30)알킬, 아릴(C1-30)아실, 치환된 (C1-30)알킬, 치환된 (C1-30)헤테로알킬, 치환된 (C2-30)아실, 치환된 (C2-30)알케닐, 치환된 (C2-30)알키닐, 치환된 아릴(C1-30)알킬 및 치환된 아릴(C1-30)아실로 이루어진 군으로부터 선택되되;단, R2가 (C1-30)아실, 아릴(C1-30)아실, 치환된 (C2-30)아실, 또는 치환된 아릴(C1-30)아실이면, R3는 H, (C1-30)알킬, (C1-30)헤테로알킬, (C2-30)알케닐, (C2-30)알키닐, 아릴(C1-30)알킬, 치환된 (C1-30)알킬, 치환된 (C1-30)헤테로알킬, 치환된 (C2-30)알케닐, 치환된 (C2-30)알키닐, 또는 치환된 아릴(C1-30)알킬이고;R4 및 R5는 각각 각 경우에 독립적으로, H, (C1-40)알킬, (C1-40)헤테로알킬, (C1-40)아실, (C2-40)알케닐, (C2-40)알키닐, 아릴(C1-40)알킬, 아릴(C1-40)아실, 치환된 (C1-40)알킬, 치환된 (C1-40)헤테로알킬, 치환된 (C1-40)아실, 치환된 (C2-40)알케닐, 치환된 (C2-40)알키닐, 치환된 아릴(C1-40)알킬, 치환된 아릴(C1-40)아실, (C1-40)알킬설포닐, 또는 C(NH)-NH2이되, R4가 (C1-40)아실, 아릴(C1-40)아실, 치환된 (C1-40)아실, 치환된 아릴(C1-40)아실, (C1-40)알킬설포닐, 또는 C(NH)-NH2이면, R5는 H 또는 (C1-C40)알킬, (C1-40)헤테로알킬, (C2-40)알케닐, (C2-40)알키닐, 아릴(C1-40)알킬, 치환된 (C1-40)알킬, 치환된 (C1-40)헤테로알킬, 치환된 (C2-40)알케닐, 치환된 (C2-40)알키닐, 또는 치환된 아릴(C1-40)알킬이고;n은 각 경우에 독립적으로, 1, 2, 3, 4, 또는 5이고;X1, X2, X3, X4, 및 X5는 각각 각 경우에 독립적으로, H, F, Cl, Br, I, (C1-10)알킬, 치환된 (C1-10)알킬, 아릴, 치환된 아릴, OH, CH2NH2, NH2, NO2, 또는 CN이되;단, 상기 화합물은 하나 이상의 비천연 아미노산에 의한 치환을 포함한다.