KR101417873B1 - 포도당 의존적인 인슐린 분비 자극성 폴리펩타이드의 유사체 - Google Patents
포도당 의존적인 인슐린 분비 자극성 폴리펩타이드의 유사체 Download PDFInfo
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Abstract
본 발명은 포도당 의존적인 인슐린 분비 자극성 폴리펩타이드의 새로운 일련의 유사체, 상기 화합물을 포함하는 약학 조성물, 및 인슐린 비의존성 당뇨병 및 비만과 같은 GIP-수용체에 의해 매개되는 증상의 치료를 위한 GIP-수용체 작용제 또는 길항제로서의 상기 화합물의 용도에 관한 것이다.
Description
본 발명은 포도당 의존적인 인슐린 분비 자극성 폴리펩타이드의 새로운 유사체, 상기 화합물을 포함하는 약학 조성물, 및 인슐린 비의존성 당뇨병 및 비만과 같은 GIP-수용체에 의해 매개되는 증상의 치료를 위한 GIP-수용체 작용제로서의 상기 화합물의 용도 분야에 관한 것이다.
포도당 의존적인 인슐린 분비 자극성 폴리펩타이드("GIP", 또한, "위 저해성 폴리펩타이드(gastric inhibitory polypeptide)"라고도 함; 서열번호 1)는 경구 영양 섭취에 반응하여 소장의 장 내분비 K 세포에 의해 소장으로 분비되는 42개의 잔기로 이루어진 펩타이드이다. GIP는 위산 분비를 저해하며, 경구 포도당 섭취 후 췌장 베타 세포에서의 인슐린 분비에 작용하는 강력한 자극제인 것으로 알려져 있다("인크레틴 효과(incretin effect)")(Creutzfeldt, W., et al ., 1979, Diabetologia, 16:75-85).
포도당과 그외 영양분의 섭취에 의해 유도되는 인슐린의 분비는 호르몬과 신경 인자에 의해 이루어진다(Creutzfeldt, W., et al ., 1985, Diabetologia, 28:565-573). 몇가지 위장 조절 펩타이드가 인크레틴으로 제시되었지만, 이들 후보 물질들 중에서, GIP와 글루카곤-유사 펩타이드 1("GLP-1")만 유일하게 식후 인슐린 분비에 관여하는 생리 자극제로 판단되는 요건들을 만족시키는 것으로 보인다(Nauck, et al ., 1989, J. Clin . Endorinol . Metab ., 69:654-662). GIP와 GLP-1의 조합 효과가 장-인슐린 축(enteroinsular axis)의 전체 인크레틴 효과를 설명하는데 충분한 것으로 확인되었다(Fehmann, H. C., et al ., 1989, FEBS Lett ., 252:109-112).
당해 기술 분야의 당업자에게 잘 알려져 있는 바와 같이, GIP의 공지된 용도와 잠재적인 용도는 여러 가지이며 다양하다. 따라서, 작용제 효과를 도출하기 위해 본 발명의 화합물을 투여하면 동일한 효과를 가질 수 있는데, GIP 그 자체로서 이용할 수 있다. GIP의 이렇듯 다양한 용도는 다음과 같이 요약할 수 있다: 1형 당뇨병, 2형 당뇨병(Visboll, T., 2004, Dan . Med . Bull ., 51:364-70), 인슐린 내성(WO 2005/082928), 비만(Green, B. D., et al ., 2004, Current Pharmaceutical Design, 10:3651-3662), 대사 장애(Gault, V. A., et al ., 2003, Biochem . Biophys. Res . Commun ., 308:207-213), 중추 신경계 질환, 신경퇴행성 질환, 울혈성 심부전, 저혈당, 및 음식 섭취 절제 및 체중 감소가 필요한 장애로 이루어진 군으로부터 선택되는 질환의 치료. GIP는, 췌도에서의 인슐린 분비를 크게 강화할 뿐만 아니라 프로인슐린의 전사 및 번역 강화를 통해 인슐린 생산을 자극하며(Wang, et al ., 1996, Mol . Cell . Endocrinol ., 116:81-87), 췌장의 베타 세포의 생장과 생존을 강화한다(Trumper, et al ., 2003, Diabetes, 52:741-750). 또한, GIP는 췌장에서의 인슐린 분비 강화 기능 외에도, 직접 혈당을 낮추는 인슐린 타겟 조직에 대한 작용: 지방 (Eckel, et al ., 1979, Diabetes, 28:1141-1142) 및 근육(O'Harte, et al ., 1998, J. Endocrinol ., 156:237-243)내 포도당의 축적 증가, 및 간에서의 포도당 생산을 저해하는 작용(Elahi, D., et al ., 1986, Can . J. Physiol. Pharmacol ., 65:A18)도 가지고 있다.
또한, 본 발명에 따른 GIP 수용체 길항제는, 동물의 장에서의 포도당 흡수를 저해, 차단 또는 감소시킨다. 이에 따라, GIP 길항제가 포함된 치료 조성물은, 인슐린 비의존형 당뇨병 환자에게 사용하여, 인간과 같은 포유류에서의 경구 포도당에 대한 내당능(tolerance)을 개선시키거나, 포유류의 장에서의 포도당 흡수를 저해, 차단 또는 감소시킴으로써 비만을 예방, 저해 또는 낮출 수 있다.
그러나, 비변형된 GIP를 치료제로 사용하는 것은, 약 2분의 짧은 생체내 반감기로 인해 제한적이다(Said and Mutt, 1970, Science, 169:1217-1218). GIP 및 GLP-1 인크레틴 2가지 모두 혈청에서 디펩티딜 펩티다제 IV ("DPPIV")에 의해 분해된다. 이러한 단백질분해에 대한 GIP의 안정성을 향상시키면, 이의 수용체에서의 GIP의 활성을 유지시킬 수 있을 뿐만 아니라, 더 중요하게는 그 중 일부가 GIP 수용체 길항제로서 작용하는 GIP 단편의 형성을 예방할 수 있다(Gault, et al ., 2002, J. Endocrinol ., 175:525-533). 변형법으로는, N-말단 티로신을 변형시켜 DPPIV에 의한 단백질분해로부터 GIP의 N-말단을 보호하는 변형법(O'Harte, et al ., 2002, Diabetologia, 45:1281-1291), 2번 위치의 알라닌을 돌연변이시키는 방법(Hinke, et al ., 2002, Diabetes, 51:656-661), 3번 위치의 글루탐산을 돌연변이시키는 방법(Gault, et al ., 2003, Biochem . Biophys . Res . Commun ., 308:207-213), 및 13번 위치의 알라닌을 돌연변이시키는 방법(Gault, et al ., 2003, Cell Biol. International, 27:41-46)이 보고되어 있다.
아래 특허 출원들은, 다양한 타겟 장기의 기능에 대한 GIP 유사체의 효과 및 이들의 치료제로서의 잠재적인 용도에 대한 내용으로 출원된 것이다.
PCT 공개번호 WO 00/58360에는 인슐린 분비를 자극하는 GIP의 펩티딜 유사체가 기술되어 있다. 특히, 이 출원에는 GIP(1-42)의 N-말단으로부터 적어도 15개의 잔기가 포함된 특정 펩티딜 유사체, 예컨대 1번, 2번 및 3번 위치에 하나의 치환 또는 변형이 실제 포함된, [Pro3]GIP(1-42)와 같은 GIP 유사체가 기술되어 있다.
PCT 공개번호 WO 98/24464에는 GIP의 서열에서 7-30번 위치에 해당되는 24개의 아미노산 폴리펩타이드로 필수적으로 구성된 GIP 길항제, 인슐린 비의존형 당뇨병의 치료 방법, 및 인슐린 비의존형 당뇨병 환자에서 내당능을 개선시키는 방법이 개시되어 있다.
PCT 공개번호 WO 03/082898에는 GIP의 C-말단의 절단형 단편과 N-말단의 변형된 유사체 뿐만 아니라 DPPIV-특이적인 절단 부위에 이웃한 아미노산들에 변형을 가지거나 또는 펩타이드 결합이 감소된 다양한 GIP 유사체들이 개시되어 있다. 이 출원에는 또한 GIP의 잠재적인 수용체 결합부들 사이에 여러가지 링커를 가진 유사체도 기술되어 있다. 이 출원의 화합물은 인슐린 비의존형 당뇨병과 비만과 같은 GIP-수용체 매개 증상을 치료하는데 유용한 것으로 주장되어 있다.
제형에서 안정적이며 생체내 혈장 반감기가 길어, 단백질분해 감수성과 소거율은 낮지만, 각각의 작용제 또는 길항제 효과를 도출하기 위한 GIP 수용체에 대한 결합 친화성은 유지하는, 개선된 GIP 유사체가 요구되고 있다. 또한, 본원에 예시된 본 발명의 화합물의 다른 치료학적 효과들 중에서도, 혈당 수치의 보다 엄격한 조절 효과는 장기간 당뇨병 합병증을 예방할 수 있으며, 따라서 환자의 삶의 질을 개선시킬 수 있다.
본 발명은 포도당 의존적인 인슐린 분비 자극성 폴리펩타이드의 새로운 일련의 유사체, 상기 화합물을 포함하는 약학 조성물, 및 인슐린 비의존성 당뇨병 및 비만과 같은 GIP-수용체에 의해 매개되는 증상의 치료를 위한 GIP-수용체 작용제 또는 길항제를 제공한다.
일 측면에서, 본 발명은 하기 식 (I)의 GIP 펩타이드 변이체에 관한 것이다:
(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-A38-A39-A40-A41-A42-A43-R1,
(I)
상기 식 (I)에서,
A1은 Tyr, 4Hppa, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;
A2는 Ala, Abu, D-Abu, Acc, Aib, β-Ala, D-Ala, Gaba, Gly, Ser, D-Ser, Thr, D-Thr, Val, 또는 D-Val이고;
A3은 Glu, Aib, Asp, NMe-Asp, Dhp, Dmt, Glu, NMe-Glu, 3Hyp, 4Hyp, 4Ktp, Pro, hPro, Thz, 또는 Tic이고;
A4는 Gly, Acc, Aib, 또는 β-Ala이고;
A5는 Thr, Acc, Aib, 또는 Ser이고;
A6은 Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X4,X5,X6,X7,X8)Phe, 또는 Trp이고;
A7은 Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, 또는 Val이고;
A8은 Ser, Aib, 또는 Thr이고;
A9는 Asp, Aib, 또는 Glu이고;
A10은 Tyr, Acc, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, 또는 (X4,X5,X6,X7,X8)Phe이고;
A11은 Ser, Acc, Aib, Nle, 또는 Thr이고;
A12는 Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, 또는 Val이고;
A13은 Ala, Acc, Aib, β-Ala, D-Ala, Gly, 또는 Ser이고;
A14는 Met, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, Phe, Tle, 또는 Val이고;
A15는 Asp, Aib, 또는 Glu이고;
A16은 Lys, Amp, Apc, Arg, hArg, Orn, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), 또는 Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이고;
A17은 Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, 또는 Val이고;
A18은 His, Amp, Arg, 2-Pal, 3-Pal, 4-Pal, Phe, 또는 Tyr이고;
A19는 Gln, Aib, 또는 Asn이고;
A20은 Gln, Aib, 또는 Asn이고;
A21은 Asp, Aib, 또는 Glu이고;
A22는 Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X4,X5,X6,X7,X8)Phe, 또는 Trp이고;
A23은 Val, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, 또는 Tle이고;
A24는 Asn, Aib, 또는 Gln이고;
A25는 Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, 또는 (X4,X5,X6,X7,X8)Phe이고;
A26은 Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X4,X5,X6,X7,X8)Phe, 또는 Tle이고;
A27은 Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X4,X5,X6,X7,X8)Phe, 또는 Tle이고;
A28은 Ala, Acc, 또는 Aib이고;
A29는 Gln, Aib, Asn이거나, 또는 결손되고;
A30은 Lys, Amp, Apc, Arg, hArg, Orn, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A31은 Gly, Acc, Aib, β-Ala, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), His, Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A32는 Lys, Amp, Apc, Arg, hArg, Orn, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A33은 Lys, Amp, Apc, Arg, hArg, Orn, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A34는 Asn, Aib, Gln, Ser, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A35는 Asp, Aib, Glu, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A36은 Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, (X4,X5,X6,X7,X8)Phe, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A37은 Lys, Amp, Apc, Arg, hArg, Orn, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A38은 His, Amp, 2-Pal, 3-Pal, 4-Pal, Phe, Tyr, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A39는 Asn, Aib, Gln, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A40은 Ile, Acc, Aib, Ser, Thr, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A41은 Thr, Acc, Aib, Asn, Gln, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A42는 Gln, Acc, Aib, Asn, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
A43은 Acc, Aib, Ala, Asp, Gln, His, Phe, Thr, Trp, HN-CH((CH2)n-N(R4R5))-C(O), Cys(숙신이미드-N-알킬), hCys(숙신이미드-N-알킬), Pen(숙신이미드-N-알킬), Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3), Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3), Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)이거나, 또는 결손되고;
R1은 OH, NH2, (C1-C30)알콕시, 또는 NH-X2-CH2-Z0이되, X2는 (C0-C30) 탄화수소 모이어티이고 Z0은 H, OH, CO2H, 또는 CONH2이고;
각각의 R2, R3, R4 및 R5는 독립적으로 H, (C1-C30)알킬, (C1-C30)헤테로알킬, (C1-C30)아실, (C2-C30)알케닐, (C2-C30)알키닐, 아릴(C1-C30)알킬, 아릴(C1-C30)아실, 치환된 (C1-C30)알킬, 치환된 (C1-C30)헤테로알킬, 치환된 (C1-C30)아실, 치환된 (C2-C30)알케닐, 치환된 (C2-C30)알키닐, 치환된 아릴(C1-C30)알킬, 및 치환된 아릴(C1-C30)아실로 이루어진 군으로부터 선택되되, R2가 (C1-C30)아실, 아릴(C1-C30)아실, 치환된 (C1-C30)아실, 또는 치환된 아릴(C1-C30)아실인 경우에는, R3는 H, (C1-C30)알킬, (C1-C30)헤테로알킬, (C2-C30)알케닐, (C2-C30)알키닐, 아릴(C1-C30)알킬, 치환된 (C1-C30)알킬, 치환된 (C1-C30)헤테로알킬, 치환된 (C2-C30)알케닐, 치환된 (C2-C30)알키닐, 또는 치환된 아릴(C1-C30)알킬이고; 또한, R4가 (C1-C30)아실, 아릴(C1-C30)아실, 치환된 (C1-C30)아실, 또는 치환된 아릴(C1-C30)아실인 경우에는, R5는 H, (C1-C30)알킬, (C1-C30)헤테로알킬, (C2-C30)알케닐, (C2-C30)알키닐, 아릴(C1-C30)알킬, 치환된 (C1-C30)알킬, 치환된 (C1-C30)헤테로알킬, 치환된 (C2-C30)알케닐, 치환된 (C2-C30)알키닐, 또는 치환된 아릴(C1-C30)알킬이며;
n은 각각의 경우에 독립적으로, 1-5의 정수이고;
s, t, x 및 y는 각각의 경우에 독립적으로, 1-30의 정수이고;
X4, X5, X6, X7 및 X8은 각각의 경우에 독립적으로, H, F, Cl, Br, I, (C1 -10)알킬, 치환된 (C1 -10)알킬, 아릴, 치환된 아릴, OH, NH2, NO2, 또는 CN이되;
단, A1이 4Hppa이면, R2 및 R3은 결손되고;
또한, 상기 화합물의 1, 2 및 3번 위치에서 오직 하나의 아미노산이 치환되거나 변형된 것이며;
또한, 식 (I)의 화합물은 (D-Ala2)hGIP(1-42), (Pro3)hGIP(1-42) (서열번호 120), (Aib3)hGIP(1-42) (서열번호 121), (Ser2)hGIP(1-42) (서열번호 122), (Abu2)hGIP(1-42) (서열번호 123), (D-Abu2)hGIP(1-42), (D-Ser2)hGIP(1-42), (D-Thr2)hGIP(1-42), 또는 (D-Val2)hGIP(1-42)가 아니다.
상기 식 (I)에 포함되는 화합물의 서브세트(A)는, 다음과 같은 화합물이다:
A1은 Tyr, 4Hppa, 또는 Orn(N-C(O)-(CH2)12-CH3)이고;
A2는 Ala, A5c, A6c, Aib, D-Ala, Gly, 또는 Ser이고;
A3은 Glu, Dhp, 3Hyp, 4Hyp, Pro, hPro, 또는 Tic이고;
A4는 Gly 또는 Aib이고;
A5는 Thr, A5c, 또는 Aib이고;
A6은 Phe 또는 A6c이고;
A7은 Ile, A5c, A6c, 또는 Aib이고;
A8은 Ser 또는 Aib이고;
A9는 Asp 또는 Aib이고;
A10은 Tyr이고;
A11은 Ser, A5c, A6c, Aib, 또는 Nle이고;
A12은 Ile, A5c, 또는 Aib이고;
A13은 Ala 또는 Aib이고;
A14는 Met, A5c, A6c, 또는 Nle이고;
A15는 Asp이고;
A16은 Lys이고;
A17은 Ile 또는 A6c이고;
A18은 His이고;
A19는 Gln이고;
A20은 Gln이고;
A21은 Asp이고;
A22는 Phe이고;
A23은 Val이고;
A24는 Asn이고;
A25는 Trp이고;
A26은 Leu 또는 A6c이고;
A27은 Leu 또는 A6c이고;
A28은 Ala 또는 Aib이고;
A29는 Gln이고;
A30은 Lys이고;
A31은 Gly, Aib, Cys(Psu), His이거나 또는 결손되고;
A32는 Lys, Cys(Psu)이거나, 또는 결손되고;
A33은 Lys, Cys(Psu)이거나, 또는 결손되고;
A34는 Asn, Cys(Psu)이거나, 또는 결손되고;
A35는 Asp, Cys(Psu)이거나, 또는 결손되고;
A36은 Trp, Cys(Psu)이거나, 또는 결손되고;
A37은 Lys, Cys(Psu)이거나, 또는 결손되고;
A38은 His, Cys(Psu)이거나, 또는 결손되고;
A39는 Asn, Cys(Psu)이거나, 또는 결손되고;
A40은 Ile, A5c, A6c, Cys(Psu)이거나, 또는 결손되고;
A41은 Thr, A5c, A6c, Aib, Cys(Psu)이거나, 또는 결손되고;
A42는 Gln이거나 결손되고;
A43은 Cys(Psu), Gln, His이거나, 또는 결손되되;
단, 이 화합물은 4-43번 위치에 하나 이상의 부가적인 아미노산 치환 또는 변형을 포함한다.
상기 서브세트 (A) 화합물의 서브세트는 A2가 D-Ala인 화합물이다.
상기 서브세트 (A) 화합물의 다른 서브세트는 A31 내지 A43가 결손된 화합물이다.
상기 서브세트 (A) 화합물의 다른 서브세트는 A2가 Ala, A5c, A6c, 또는 Gly이고; A3가 Glu, Dhp, 3Hyp, 4Hyp, hPro, 또는 Tic인 화합물이다.
본 발명의 다른 서브세트는, 천연 hGIP 아미노산 서열의 N 말단에서부터 처음 30개의 연속적인 아미노산 잔기들의 서열로 필수적으로 구성된 화합물로서, 상기 서열은 2번 위치에 A5c, A6c, Aib, D-Ala, Gly 또는 Ser 치환을 포함하며, 3-30번 위치에 하나 이상의 아미노산 치환 또는 변형을 포함하는, 화합물을 포함한다.
본 발명의 바로 위의 측면에 대한 화합물의 서브세트는, A2가 Aib이고; A3가 Pro이고; A7, A11, A13 및 A14 중 하나 이상이 천연 GIP에서의 대응되는 위치의 아미노산이 아닌, 화합물이다.
본 발명의 또다른 측면은, 2번 위치에 A5c, A6c, Aib, D-Ala, Gly 또는 Ser 치환을 포함하며, 1번 및 3-42번 위치에 하나 이상의 아미노산 치환 또는 변형을 포함하는, GIP 유사체를 포함한다.
본 발명의 상기 측면에 대한 화합물의 서브세트는, A2가 Aib인 화합물이다.
식 (I)의 바람직한 화합물은 다음과 같다:
실시예 1: (Aib2 , 11)hGIP(1-42)-OH (서열번호 4);
실시예 2: (Aib2 , 9)hGIP(1-42)-OH (서열번호 5);
실시예 3: (Aib2 , 7)hGIP(1-42)-OH (서열번호 6);
실시예 4: (Aib2 , 5)hGIP(1-42)-OH (서열번호 7);
실시예 5: (Aib2, A5c5)hGIP(1-42)-OH (서열번호 8);
실시예 6: (Aib2, A5c7)hGIP(1-42)-OH (서열번호 9);
실시예 7: (Aib2, A5c12)hGIP(1-42)-OH (서열번호 10);
실시예 8: (Aib2 , 12)hGIP(1-42)-OH (서열번호 11);
실시예 9: (Aib2 , 8)hGIP(1-42)-OH (서열번호 12);
실시예 10: (Aib2 , 4)hGIP(1-42)-OH (서열번호 13);
실시예 11: (Aib2, A5c5)hGIP(1-30)-NH2 (서열번호 14);
실시예 12: (Aib2, A5c7)hGIP(1-30)-NH2 (서열번호 15);
실시예 13: (Aib2, A5c12)hGIP(1-30)-NH2 (서열번호 16);
실시예 14: (Aib2 , 4)hGIP(1-30)-NH2 (서열번호 17);
실시예 15: (Aib2 , 5)hGIP(1-30)-NH2 (서열번호 18);
실시예 16: (Aib2 , 7)hGIP(1-30)-NH2 (서열번호 19);
실시예 17: (Aib2 , 8)hGIP(1-30)-NH2 (서열번호 20);
실시예 18: (Aib2 , 9)hGIP(1-30)-NH2 (서열번호 21);
실시예 19: (Aib2 , 11)hGIP(1-30)-NH2 (서열번호 22);
실시예 20: (Aib2 , 12)hGIP(1-30)-NH2 (서열번호 23);
실시예 21: (Aib2 , 13, A6c7, Nle14)hGIP(1-42)-OH (서열번호 24);
실시예 22: (Aib2 , 31, A6c7)hGIP(1-42)-OH (서열번호 25);
실시예 23: (Aib2 , 41, A6c7)hGIP(1-42)-OH (서열번호 26);
실시예 24: (Aib2 , 31, A6c7, Nle14)hGIP(1-42)-OH (서열번호 27);
실시예 25: (Aib2 , 41, A6c7, Nle14)hGIP(1-42)-OH (서열번호 28);
실시예 26: (Aib2, A6c7, 26, Nle14)hGIP(1-42)-OH (서열번호 29);
실시예 27: (Aib2, A6c7, 27, Nle14)hGIP(1-42)-OH (서열번호 30);
실시예 28: (Aib2, A6c7, 40, Nle14)hGIP(1-42)-OH (서열번호 31);
실시예 29: (Aib2, A6c7, 41, Nle14)hGIP(1-42)-OH (서열번호 32);
실시예 30: (Aib2 , 28, A6c7, Nle14)hGIP(1-42)-OH (서열번호 33);
실시예 31: (Aib2, A6c7, Nle14)hGIP(1-30)-NH2 (서열번호 34);
실시예 32: (Aib2, A5c7, Nle14)hGIP(1-30)-NH2 (서열번호 35);
실시예 33: (Aib2 , 11, Nle14)hGIP(1-30)-NH2 (서열번호 36);
실시예 34: (A5c2, 7, Nle14)hGIP(1-30)-NH2 (서열번호 37);
실시예 35: (Aib2, A5c7, 14)hGIP(1-30)-NH2 (서열번호 38);
실시예 36: (A6c2, 7, Nle14)hGIP(1-30)-NH2 (서열번호 39);
실시예 37: (Aib2, A6c7, 17, Nle14)hGIP(1-42)-OH (서열번호 40);
실시예 38: (Aib2 , 11, A6c14)hGIP(1-30)-NH2 (서열번호 41);
실시예 39: (Aib2, A6c7, 14)hGIP(1-30)-NH2 (서열번호 42);
실시예 40: (A5c2, Nle14)hGIP(1-42)-OH (서열번호 43);
실시예 41: (Aib2 , 11, A6c14)hGIP(1-42)-OH (서열번호 44);
실시예 42: (Aib2, A6c14)hGIP(1-42)-OH (서열번호 45);
실시예 43: (Aib2, A6c7)hGIP(1-42)-OH (서열번호 46);
실시예 44: (Aib2, A5c7, A6c14)hGIP(1-42)-OH (서열번호 47);
실시예 45: (Aib2 , 11, Nle14)hGIP(1-42)-OH (서열번호 48);
실시예 46: (Aib2, A5c11)hGIP(1-30)-NH2 (서열번호 49);
실시예 47: (Aib2 , 13)hGIP(1-30)-NH2 (서열번호 50);
실시예 48: (Aib2, A5c11, A6c14)hGIP(1-30)-NH2 (서열번호 51);
실시예 49: (Aib2 , 13, Nle14)hGIP(1-30)-NH2 (서열번호 52);
실시예 50: (Aib2, A5c11, Nle14)hGIP(1-30)-NH2 (서열번호 53);
실시예 51: (Aib2, A6c7, 14)hGIP(1-42)-OH (서열번호 54);
실시예 52: (Aib2, A6c7)hGIP(1-30)-NH2 (서열번호 55);
실시예 53: (Aib2, A5c11)hGIP(1-42)-OH (서열번호 56);
실시예 54: (Aib2, A5c11, Nle14)hGIP(1-42)-OH (서열번호 57);
실시예 55: (Aib2, A6c7, Nle14)hGIP(1-42)-OH (서열번호 58);
실시예 56: (A5c2, 7, A6c14)hGIP(1-42)-OH (서열번호 59);
실시예 57: (Aib2 , 13, Nle14)hGIP(1-42)-OH (서열번호 60);
실시예 58: (Aib2, A5c7, Nle14)hGIP(1-42)-OH (서열번호 61);
실시예 59: (Aib2, A5c7, 14)hGIP(1-42)-OH (서열번호 62);
실시예 60: (Aib2 , 13)hGIP(1-42)-OH (서열번호 63);
실시예 61: (Aib2, A5c11, A6c14)hGIP(1-42)-OH (서열번호 64);
실시예 62: (Pro3, Aib13, Nle14)hGIP(1-42)-OH (서열번호 65);
실시예 63: (hPro3, Aib13, Nle14)hGIP(1-42)-OH (서열번호 66);
실시예 64: (Dhp3, Aib13, Nle14)hGIP(1-42)-OH (서열번호 67);
실시예 65: (hPro3, Aib13)hGIP(1-42)-OH (서열번호 68);
실시예 66: (Tic3, Aib13)hGIP(1-42)-OH (서열번호 69);
실시예 67: (4Hyp3, Aib13)hGIP(1-42)-OH (서열번호 70);
실시예 68: (4Hyp3, Aib13, Nle14)hGIP(1-42)-OH (서열번호 71);
실시예 69: (Tic3, Aib13, Nle14)hGIP(1-42)-OH (서열번호 72);
실시예 70: (3Hyp3, Aib13, Nle14)hGIP(1-42)-OH (서열번호 73);
실시예 71: (Tic3, A6c14)hGIP(1-42)-OH (서열번호 74);
실시예 72: (hPro3, A6c14)hGIP(1-42)-OH (서열번호 75);
실시예 73: Aib2, A6c7, Cys(Psu)41]hGIP(1-42)-OH (서열번호 76);
실시예 74: (hPro3, A5c11)hGIP(1-42)-OH (서열번호 77);
실시예 75: (Pro3, Aib13)hGIP(1-42)-OH (서열번호 78);
실시예 76: (Pro3, A5c7, 14)hGIP(1-42)-OH (서열번호 79);
실시예 77: (Pro3, A5c11)hGIP(1-42)-OH (서열번호 80);
실시예 78: [Aib2, A6c7, Cys(Psu)40]hGIP(1-42)-OH (서열번호 81);
실시예 79: [Aib2, A6c7, Cys(Psu)39]hGIP(1-42)-OH (서열번호 82);
실시예 80: [Aib2, A6c7, Cys(Psu)38]hGIP(1-42)-OH (서열번호 83);
실시예 81: [Aib2, A6c7, Cys(Psu)36]hGIP(1-42)-OH (서열번호 84);
실시예 82: (Tic3, A5c11)hGIP(1-42)-OH (서열번호 85);
실시예 83: (hPro3, A5c11, A6c14)hGIP(1-42)-OH (서열번호 86);
실시예 84: (4Hyp3, A6c14)hGIP(1-42)-OH (서열번호 87);
실시예 85: [Aib2, A6c7, Cys(Psu)35]hGIP(1-42)-OH (서열번호 88);
실시예 86: [Aib2, A6c7, Cys(Psu)34]hGIP(1-42)-OH (서열번호 89);
실시예 87: (4Hyp3, A5c11)hGIP(1-42)-OH (서열번호 90);
실시예 88: (4Hyp3, A5c11, A6c14)hGIP(1-42)-OH (서열번호 91);
실시예 89: (Tic3, A5c11, A6c14)hGIP(1-42)-OH (서열번호 92);
실시예 90: [Aib2, A6c7, Cys(Psu)31]hGIP(1-42)-OH (서열번호 93);
실시예 91: (Pro3, A6c14)hGIP(1-42)-OH (서열번호 94);
실시예 92: (Pro3, A5c11, Nle14)hGIP(1-30)-OH (서열번호 95);
실시예 93: (Aib2, A6c7, Gln43)hGIP(1-43)-OH (서열번호 96);
실시예 94: [Aib2, A6c7, Cys(Psu)32]hGIP(1-42)-OH (서열번호 97);
실시예 95: [Aib2, A6c7, Cys(Psu)43]hGIP(1-43)-OH (서열번호 98);
실시예 96: (Pro3, A5c11, A6c14)hGIP(1-30)-NH2 (서열번호 99);
실시예 97: (Pro3, A6c7)hGIP(1-30)-NH2 (서열번호 100);
실시예 98: [(Pro3, A5c11])hGIP(1-30)-NH2 (서열번호 101);
실시예 99: [Aib2, A6c7, Cys(Psu)33]hGIP(1-42)-OH (서열번호 102);
실시예 100: [Aib2, A6c7, Cys(Psu)37]hGIP(1-42)-OH (서열번호 103);
실시예 101: [(4Hppa1, Aib13])hGIP(1-42)-OH (서열번호 104);
실시예 102: [(Pro3, A5c11, A6c14])hGIP(1-42)-OH (서열번호 105);
실시예 103: [Orn1(N-C(O)-(CH2)12-CH3), A6c7]hGIP(1-42)-OH (서열번호 106);
실시예 104: (D-Ala2, A5c11,40)hGIP(1-42)-OH;
실시예 105: (D-Ala2, A5c11, His43)hGIP(1-43)-OH;
실시예 106: (D-Ala2, A5c11, 41)hGIP(1-42)-OH;
실시예 107: (D-Ala2, A6c11, 14, 41)hGIP(1-42)-OH;
실시예 108: (Aib2 , 13, Pro3, Nle14)hGIP(1-30)-NH2 (서열번호 107);
실시예 109: (Aib2, Pro3, A6c7)hGIP(1-30)-NH2 (서열번호 108);
실시예 110: (Aib2, Pro3, A5c11)hGIP(1-30)-NH2 (서열번호 109);
실시예 111: (Aib2, Pro3, A5c11, Nle14)hGIP(1-30)-NH2 (서열번호 110);
실시예 112: (Aib2, Pro3, A5c11, A6c14)hGIP(1-30)-NH2 (서열번호 111);
실시예 113: (NMe-Tyr1, Aib2, A5c11, Nle14)hGIP(1-42)-OH (서열번호 112);
실시예 114: (Gly2, A6c11, 14, 41)hGIP(1-42)-OH (서열번호 113);
실시예 115: (Gly2, Aib13, A5c40)hGIP(1-42)-OH (서열번호 114);
실시예 116: (Gly2, A5c11, 41)hGIP(1-42)-OH (서열번호 115);
실시예 117: (Gly2, A5c11, His43)hGIP(1-43)-OH (서열번호 116);
실시예 118: (Gly2, A5c11, Nle14, His43)hGIP(1-43)-OH (서열번호 117);
실시예 119: (D-Ala2, A5c11, Nle14, His43)hGIP(1-43)-OH;
실시예 120: (D-Ala2, A5c11, 14, His43)hGIP(1-43)-OH;
실시예 121: (D-Ala2, A5c11, 14)hGIP(1-30)-NH2;
실시예 122: (D-Ala2, A5c11, His31)hGIP(1-31)-NH2; 및
실시예 123: (Aib2, A5c11, 14, His43)hGIP(1-43)-OH (서열번호 118).
본 발명의 다른 측면에서, 상기 요약 개시되고 첨부된 청구항에 청구된 본 발명의 화합물은, 공유 연결된 PEG 모이어티를 더 포함할 수 있으며, 이때 PEG 모이어티는 Cys(말레이미드), hCys(말레이미드), 또는 Pen(말레이미드) 링커를 통해 상기 화합물에 연결되어, Cys(숙신이미드-N-PEG), hCys(숙신이미드-N-PEG), 또는 Pen(숙신이미드-N-PEG)를 형성하며, "숙신이미드-N-PEG"는 하기에 명시된 바와 같이 선형 또는 분지형이다. 이러한 PEG 모이어티는 평균 분자량이 약 2,000 내지 약 80,000이며, 바람직하게는, PEG 모이어티는 5K PEG, 10K PEG, 20K PEG, 30K PEG, 40K PEG, 50K PEG, 및 60K PEG로 이루어진 군으로부터 선택되며, Cys(숙신이미드-N-5K PEG), Cys(숙신이미드-N-10K PEG), Cys(숙신이미드-N-20K PEG), Cys(숙신이미드-N-30K PEG), Cys(숙신이미드-N-40K PEG), Cys(숙신이미드-N-50K PEG), Cys(숙신이미드-N-60K PEG), hCys(숙신이미드-N-5K PEG), hCys(숙신이미드-N-10K PEG), hCys(숙신이미드-N-20K PEG), hCys(숙신이미드-N-30K PEG), hCys(숙신이미드-N-40K PEG), hCys(숙신이미드-N-50K PEG), hCys(숙신이미드-N-60K PEG), Pen(숙신이미드-N-5K PEG), Pen(숙신이미드-N-10K PEG), Pen(숙신이미드-N-20K PEG), Pen(숙신이미드-N-30K PEG), 또는 Pen(숙신이미드-N-40K PEG), Pen(숙신이미드-N-50K PEG), 또는 Pen(숙신이미드-N-60K PEG)를 형성한다.
페길화(PEGylation)는 아미노산 잔기 16, 30 및 31-43번 위치 중 어느 하나에서 이루어지며, 바람직하게는 아미노산 잔기 32, 33 및 43번 위치에서 이루어지며, Cys(숙신이미드-N-PEG), hCys(숙신이미드-N-PEG), 또는 Pen(숙신이미드-N-PEG)가 상기 아미노산 잔기 위치 중 어느 하나에 위치되게 된다.
또한, 상기 식 (I)은 A44-A47번 위치에 페길화된 부위를 제공하는 것으로 확장될 수 있다. 본 발명의 이러한 페길화된 화합물의 C-말단은, 아미드화될 수 있으며, 예컨대, (Aib2 , 11) hGIP(1-42)-NH2 (서열번호 119)일 수 있으며, 또는 유리 산, 예컨대, (Aib2 , 11)hGIP(1-42)-OH로 존재할 수 있다.
본 발명은 포도당 의존적인 인슐린 분비 자극성 폴리펩타이드의 새로운 일련의 유사체, 상기 화합물을 포함하는 약학 조성물, 및 인슐린 비의존성 당뇨병 및 비만과 같은 GIP-수용체에 의해 매개되는 증상의 치료를 위한 GIP-수용체 작용제 또는 길항제를 제공한다.
본원에서는 통상적으로 이해되는 약어를 사용한다:
Abu α-아미노부티르산
Acc 1-아미노-1-사이클로(C3-C9)알킬 카르복시산
A3c 1-아미노-1-사이클로프로판카르복시산
A4c 1-아미노-1-사이클로부탄카르복시산
A5c 1-아미노-1-사이클로펜탄카르복시산
A6c 1-아미노-1-사이클로헥산카르복시산
Act 4-아미노-4-카르복시테트라하이드로피란
Ado 12-아미노도데칸산
Aib α-아미노이소부티르산
Aic 2-아미노인단-2-카르복시산
Ala 또는 A 알라닌
β-Ala β-알라닌
Amp 4-아미노-페닐알라닌
Apc 4-아미노-4-카르복시피페리딘
Arg 또는 R 아르기닌
hArg 호모아르기닌
Asn 또는 N 아스파라긴
Asp 또는 D 아스파르트산
Aun 11-아미노운데칸산
Ava 5-아미노발레르산
Cha β-사이클로헥실알라닌
Cys 또는 C 시스테인
Dhp 3,4-데하이드로프롤린
Dmt 5,5-디메틸티아졸리딘-4-카르복시산
Gaba 감마-아미노부티르산
Gln 또는 Q 글루타민
Glu 또는 E 글루탐산
Gly 또는 G 글리신
His 또는 H 히스티딘
4Hppa 3-(4-하이드록시페닐)프로피온산
3Hyp 3-하이드록시프롤린
4Hyp 4-하이드록시프롤린
hPro 호모프롤린
Ile 또는 I 이소루신
4Ktp 4-케토프롤린
Leu 또는 L 루신
Lys 또는 K 라이신
Met 또는 M 메티오닌
Nle 노르루신
NMe-Tyr N-메틸-티로신
1Nal 또는 1-Nal β-(1-나프틸)알라닌
2Nal 또는 2-Nal β-(2-나프틸)알라닌
Nle 노르루신
Nva 노르발린
Orn 오르니틴
2Pal 또는 2-Pal β-(2-피리디닐)알라닌
3Pal 또는 3-Pal β-(3-피리디닐)알라닌
4Pal 또는 4-Pal β-(4-피리디닐)알라닌
Pen 페니실린아민
Phe 또는 F 페닐알라닌
(3,4,5F)Phe 3,4,5-트리플루오로페닐알라닌
(2,3,4,5,6)Phe 2,3,4,5,6-펜타플루오로페닐알라닌
Pro 또는 P 프롤린
Psu N-프로필숙신이미드
Ser 또는 S 세린
Taz β-(4-티아졸릴)알라닌
3Thi β-(3-티에닐)알라닌
Thr 또는 T 트레오닌
Thz 티오프롤린
Tic 테트라하이드로이소퀴놀린-3-카르복시산
Tle tert-루신
Trp 또는 W 트립토판
Tyr 또는 Y 티로신
Val 또는 V 발린
본원에 사용되는 특정한 다른 약어들은 다음과 같이 정의된다:
Acn: 아세토니트릴
Boc: tert-부틸옥시카르보닐
BSA: 소 혈청 알부민
DCM: 디클로로메탄
DIPEA: 디이소프로필에틸 아민
DMF: 디메틸포름아미드
ESI: 전기분무 이온화법
Fmoc: 9-플루오레닐메틸옥시카르보닐
HBTU: 2-(1H-벤조트리아졸-1-일)-1,1,3,3-테트라메틸우로늄 헥사플루오로포스페이트
HOBT: 1-하이드록시-벤조트리아졸
HPLC: 고성능 액체 크로마토그래피
IBMX: 이소부틸메틸잔틴
LC-MS: 액체 크로마토그래피-질량 분광측정기
Mtt: 메틸트리틸
NMP: N-메틸피롤리돈
5K PEG: 링커와 같은 다른 작용기나 모이어티를 포함할 수 있으며, 후술된 바와 같이 선형 또는 분지형일 수 있는, 총 평균 분자량이 약 5,000인 폴리에틸렌 글리콜
10K PEG: 링커와 같은 다른 작용기나 모이어티를 포함할 수 있으며, 후술된 바와 같이 선형 또는 분지형일 수 있는, 총 평균 분자량이 약 10,000인 폴리에틸렌 글리콜
20K PEG: 링커와 같은 다른 작용기나 모이어티를 포함할 수 있으며, 후술된 바와 같이 선형 또는 분지형일 수 있는, 총 평균 분자량이 약 20,000인 폴리에틸렌 글리콜
30K PEG: 링커와 같은 다른 작용기나 모이어티를 포함할 수 있으며, 후술된 바와 같이 선형 또는 분지형일 수 있는, 총 평균 분자량이 약 30,000인 폴리에틸렌 글리콜
40K PEG: 링커와 같은 다른 작용기나 모이어티를 포함할 수 있으며, 후술된 바와 같이 선형 또는 분지형일 수 있는, 총 평균 분자량이 약 40,000인 폴리에틸렌 글리콜
50K PEG: 링커와 같은 다른 작용기나 모이어티를 포함할 수 있으며, 후술된 바와 같이 선형 또는 분지형일 수 있는, 총 평균 분자량이 약 50,000인 폴리에틸렌 글리콜
60K PEG: 링커와 같은 다른 작용기나 모이어티를 포함할 수 있으며, 후술된 바와 같이 선형 또는 분지형일 수 있는, 총 평균 분자량이 약 60,000인 폴리에틸렌 글리콜
tBu: tert-부틸
TIS: 트리이소프로필실란
Trt: 트리틸
TFA: 트리플루오로 아세트산
Z: 벤질옥시카르보닐
"Cys(숙신이미드-N-알킬)"은 하기 구조로 표시된다:
"Cys(Psu)"은 하기 구조로 표시된다:
"Orn(N-C(O)-(CH2)12-CH3)"은 하기 구조로 표시된다:
"Cys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3)"은 하기 구조(x = 1-30, 및 y = 1-30)로 표시된다:
"hCys(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3)"는 하기 구조(x = 1-30, 및 y = 1-30)로 표시된다:
"Pen(숙신이미드-N-(CH2)x-C(O)-NH-(CH2)y-CH3)"는 하기 구조(x = 1-30, 및 y = 1-30)로 표시된다:
"Cys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)"는 하기 구조(s = 1-30, 및 t = 1-30)로 표시된다:
"hCys(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)"는 하기 구조(s = 1-30, 및 t = 1-30)로 표시된다:
"Pen(숙신이미드-N-(CH2)s-NH-C(O)-(CH2)t-CH3)"는 하기 구조(s = 1-30, 및 t = 1-30)로 표시된다:
"Cys(숙신이미드-N-PEG)"는 하기 구조로 표시된다:
"hCys(숙신이미드-N-PEG)"는 하기 구조로 표시된다:
"Pen(숙신이미드-N-PEG)"는 하기 구조로 표시된다:
"Cys(숙신이미드-N-(CH2)2-C(O)NH-(CH2)3-PEG)"는 하기 구조로 표시된다:
"Cys(숙신이미드-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(PEG)-CH2-PEG)"는 하기 구조로 표시된다:
본원에서, N-말단 아미노산을 제외하고는, 아미노산의 모든 약어(예, Ala)는 구조 -NH-C(R)(R')-CO-를 유지하며, 여기에서 R 및 R'은 각각 독립적으로 수소 또는 아미노산의 측쇄(예, Ala의 경우, R = CH3 및 R' = H)이거나, R 및 R'은 연결되어 고리 시스템을 형성할 수 있다. N-말단 아미노산의 경우, 약어는 (R2R3)N-C(R)(R')-CO- 구조를 지칭하며, 이때 R2 및 R3는 상기 식 (I)에서 정의된 바와 같다.
용어 "(C1-C30)탄화수소 모이어티"는 알킬, 알케닐 및 알키닐을 포함하며, 알케닐 및 알키닐의 경우에는 C2-C30이다.
또한, 본 발명의 펩타이드는 다른 형태, 예컨대 괄호 안에 위치한 천연 서열로부터 치환된 아미노산이 있는, (A5c2)hGIP(1-42)-OH (서열번호 3)(hGIP에서 Ala2 대신 A5c2)으로 나타낸다. 괄호 안의 숫자는 펩타이드에 존재하는 아미노산의 갯수이다(예, hGIP에서, hGIP(1-42)-OH (서열번호 1)는 아미노산 1에서 42qjs의 펩타이드 서열임). hGIP(1-30)-NH2 (서열번호 2)에서 "NH2"는, 펩타이드의 C-말단이 아미드화된 것이며; hGIP(1-42) (서열번호 1) 또는 hGIP(1-42)-OH (서열번호 1)는 C-말단이 유리산임을 의미한다.
인간 GIP ("hGIP")는 하기 아미노산 서열을 가진다:
"아실"은 R"이 H, 알킬, 치환된 알킬, 헤테로알킬, 치환된 헤테로알킬, 알케닐, 치환된 알케닐, 아릴, 알킬아릴 또는 치환된 알킬아릴인, R"-C(O)-이다.
"알킬"은 복수의 탄소 원자가 존재하다면 단일 결합으로 연결되어 있는, 하나 이상의 탄소 원자를 포함하고 있는 탄화수소기이다. 알킬 탄화수소기는 직쇄일 수 있거나, 또는 하나 이상의 분지 또는 사이클기를 포함할 수도 있다.
"치환된 알킬"은 탄화수소기에서 하나 이상의 수소 원자가, 할로겐(즉, F, Cl, Br 및 I), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, 및 할로겐, -CF3, -OCH3, -OCF3 및 -(CH2)0-20-COOH로 선택적으로 치환된 -C1 -20 알킬로 이루어진 군으로부터 선택된 하나 이상의 치환기로 치환된, 알킬이다. 여러가지 구현예에서, 1, 2, 3 또는 4개의 치환기가 존재한다. -(CH2)0-20-COOH이 존재하면, 알킬 산이 생성된다. -(CH2)0-20-COOH를 포함하는 알킬 산 또는 -(CH2)0-20-COOH로 이루어진 알킬 산의 예로는, 2-노르보난 아세트산, tert-부티르산 및 3-사이클로펜틸 프로피온산을 포함한다.
"헤테로알킬"은 탄화수소기에서 하나 이상의 탄소 원자가 아미노, 아미도, -O-, -S- 또는 카르보닐 중 하나 이상으로 치환된 알킬이다. 여러가지 예에서, 1 또는 2개의 헤테로원자가 존재한다.
"치환된 헤테로알킬"은 탄화수소기에서 하나 이상의 수소 원자가 할로겐, -OH, -CN, -SH, -NH2, -NHCH3, -NO2, 및 할로겐, -CF3, -OCH3, -OCF3 및 -(CH2)0-20-COOH로 치환된 -C1 -20 알킬로 이루어진 군으로부터 선택된 하나 이상의 치환기로 치환된, 헤테로알킬이다. 여러가지 예에서, 1, 2, 3 또는 4개의 치환기가 존재한다.
"알케닐"은 하나 이상의 탄소-탄소 이중 결합이 존재하는 2개 이상의 탄소로 구성된 탄화수소기이다. 알케닐 탄화수소기는 직쇄이거나, 또는 하나 이상의 분지 또는 사이클기를 포함할 수도 있다.
"치환된 알케닐"은 하나 이상의 수소가 할로겐, -OH, -CN, -SH, -NH2, -NHCH3, -NO2, 및 할로겐, -CF3, -OCH3, -OCF3 및 -(CH2)0-20-COOH로 치환된 -C1 -20 알킬로 이루어진 군으로부터 선택된 하나 이상의 치환기로 치환된, 알케닐이다. 여러가지 예에서, 1, 2, 3 또는 4개의 치환기가 존재한다.
"아릴"은 최대 3개의 공액된(conjugated) 또는 융합된(fused) 고리 시스템을 포함하며, 공액된 파이-전자 시스템(pi-electron system)을 가지고 있는 하나 이상의 고리를 가진 선택적으로 치환된 방향족 기를 일컫는다. 아릴은 카르보사이클 아릴, 헤테로사이클 아릴 및 비아릴기를 포함한다. 바람직하기로는, 아릴은 5 또는 6원환이다. 헤테로사이클 아릴에서 바람직한 원자는, 하나 이상의 황, 산소 및/또는 질소이다. 아릴의 예로는, 페닐, 1-나프틸, 2-나프틸, 인돌, 퀴놀린, 2-이미다졸 및 9-안트라센이 있다. 아릴 치환기는 -C1 -20 알킬, -C1 -20 알콕시, 할로겐, -OH, -CN, -SH, -NH2, -NO2, 및 할로겐, -CF3, -OCF3 또는 -(CH2)0-20-COOH로 치환된 -C1-20 알킬로 이루어진 군으로부터 선택된다. 여러가지 예에서, 아릴은 0, 1, 2, 3 또는 4개의 치환기를 포함한다.
"알킬아릴"은 "아릴"이 연결된 "알킬"이다.
합성
본 발명의 펩타이드는, 표준적인 고상 펩타이드 합성으로 제조할 수 있다. 예로, Stewart, J. M., et al ., 1984, Solid Phase Synthesis, Pierce Chemical Co., 2d ed을 참조한다. R1이 NH-X2-CH2-CONH2인 경우, 즉, Z0 = CONH2이면, 펩타이드의 합성은 링크 아미드 MBSA 수지에 커플링된 Fmoc-HN-X2-CH2- CONH2를 이용하여 개시한다. R1이 NH-X2-CH2-COOH, 즉, Z0 = COOH이면, 펩타이드 합성은 Wang 수지에 커플링된 Fmoc-HN-X2-CH2-COOH를 이용하여 개시한다. 이러한 특정 단계에서, 2 몰 당량의 Fmoc-HN-X2-COOH, HBTU 및 HOBt와, 10 몰 당량의 DIPEA가 사용된다. 커플링 시간은 약 8시간이다.
A5c, A6c, 및/또는 Aib가 포함된 본 발명의 GIP 유사체 합성에서, 이들 잔기와 이 잔기 바로 다음의 잔기의 커플링 시간은 2시간이다.
상기 일반식의 치환기 R2 및 R3는 당해 기술 분야에 공지된 표준 방법에 의해 N-말단 아미노산의 유리 아민 A1에 부착할 수 있다. 예로, 알킬기, 예컨대, (C1-C30)알킬은 환원성 알킬화를 이용하여 부착할 수 있다. 하이드록시알킬기, 예컨대, (C1-C30)하이드록시알킬은 또한 유기 하이드록시기가 tert-부틸 에스테르로 보호된, 환원성 알킬화를 이용하여 부착할 수 있다. 아실기, 예컨대, -C(O)X3는, 약 1시간 동안 메틸렌 클로라이드 중에서 완비된 수지(completed resin)를 유리산 및 디이소프로필카르보디이미드 둘다와 혼합함으로써 N-말단 아미노산의 유리 아민에, 유리 산, 예컨대, -X3COOH를 커플링함으로써 부착할 수 있다. 유리 산에 유리 하이드록시기, 예컨대, 3-플루오로-4-하이드록시페닐아세트산이 포함된 경우, 커플링은 3 몰 당량의 HOBT를 첨가하여 수행하여야 한다.
하기 구현예는, 당해 기술 분야의 당업자들에게 잘 알려져 있는 방법인, 본 발명의 펩타이드를 제조하기 위한 합성 방법을 나타낸다. 또한, 당해 기술 분야의 당업자에게는 다른 방법들도 공지되어 있다. 구현예는 예시하기 위한 것일 뿐 어떠한 방식으로도 본 발명의 범위를 한정하는 것은 아니다.
실시예
73: [
Aib
2
, A6c
7
, Cys(
Psu
)
41
]
hGIP
(1-42)-
OH
고상 펩타이드 합성을 이용하여, 리버르티 펩타이드 합성기(CEM; Matthews, NC, USA)에서 마이크로웨이브-조합 Fmoc 화학법을 이용하여 펩타이드를 0.1 mmole 수준으로 조립하였다. 프리-로드한 Fmoc-Gln(Trt)-Wang 수지(0.59 mmole/g; Novabiochem, San Diego, CA, USA)를 이용하여, C-말단 펩타이드를 제조하였다. 수지(0.17 g)를 15 ml의 디메틸포름아미드(DMF)와 함께 50 ml 코니칼 튜브에 넣고, 합성기에서 수지 위치에 주입하였다. 그 후, 수지는 자동 공정을 통해 반응 용기로 정량적으로 이동시켰다. 0.1 mmole 수준의 합성을 위한 표준적인 리버르티 합성 프로토콜을 사용하였다. 이 프로토콜에는, DMF 중의 0.1 M N-하이드록시벤조트리아졸(HOBT)이 함유된, 20% 피페리딘 7 ml을 먼저 처리하여, N-말단 Fmoc 모이어티를 탈보호화하는 단계가 포함되어 있다. 일차 탈보호 단계는 마이크로웨이브 파워(45 watts, 최대 온도: 75℃)와 질소 버블링(3초 실시/7초 휴식)을 이용하여 30초간 수행하였다. 그 후, 반응 용기를 배수시키고, 1차 처리와 동일하지만 3분간 실시하는 2차 피페리딘 처리를 수행하였다. 이후, 수지를 배수시키고, DMF로 여러번 완전히 세정하였다. DMF 중의 0.2 M 스톡 용액으로 준비한 보호된 아미노산 Fmoc-Thr(tBu)-OH를 첨가(2.5 ml, 5 eq.)한 다음, DMF 중의 0.45M (4.5 eq.) HBTU [2-(1H-벤조-트리아졸-1-일)-1,1,3,3-테트라메틸우로늄 헥사플루오로포스페이트] 1.0 ml을 첨가하였다. 이 후, NMP(N-메틸피롤리디논) 중의 2M (10 eq.) DIPEA(디이소프로필에틸아민) 0.5 ml을 첨가하였다. 20와트의 마이크로웨이브 파워를 이용하여, 최대 75℃에서 동일한 질소 버블링율로 5분간, 커플링 단계를 수행하였다.
처음 커플링 단계 다음에, 반응 용기를 배수시켜 버리고, 커플링 단계를 반복하였다. 사이클 1과 유사하게 사이클 2를 개시하였다. 아미노산 모두 유사하게 도입하였고, 전체 서열에 이중-커플링 전략을 적용하였다. 사이클 1-3, 19-20, 25-26, 및 30-39에는 커플링 단계 바로 다음 단계로 캡핑 공정을 포함시켰다. 캡핑은, NMP 중의 0.015 M HOBT가 포함된 0.5 M 무수 아세트산 7 ml을 2 M DIPEA 용액 2 ml과 함께 첨가하여, 다단계 마이크로웨이브 프로토콜(50와트의 파워로 30초간(최대 온도 65 ℃) -> 마이크로웨이브 파워를 끄고 30초 -> 제2 라운드: (50와트) 마이크로웨이브 파워로 30초간 -> 마이크로웨이브 파워 끈 상태로 다시 30초 수행)로 수행하여, 실시하였다. 그런 후, 수지를 배수시키고, DMF로 잘 헹구었다. 다음 아미노산(Advanced Chemtech, Louisville, KY, USA)을 사용하였다: 사이클 1: Fmoc-Cys(Trt)-OH; 사이클 2: Fmoc-Ile-OH; 사이클 3: Fmoc-Asn(Trt)-OH; 사이클 4: Fmoc-His(Trt)-OH; 사이클 5: Fmoc-Lys(Boc)-OH; 사이클 6: Fmoc-Trp(Boc)-OH; 사이클 7: Fmoc-Asp(OtBu)-OH; 사이클 8: Fmoc-Asn(Trt)-OH; 사이클 9: Fmoc-Lys(Boc)-OH; 사이클 10: Fmoc-Lys(Boc)-OH; 사이클 11: Fmoc-Gly-OH; 사이클 12: Fmoc-Lys(Boc)-OH; 사이클 13: Fmoc-Gln(Trt)-OH; 사이클 14: Fmoc-Ala-OH; 사이클 15: Fmoc-Leu-OH; 사이클 16: Fmoc-Leu-OH; 사이클 17: Fmoc-Trp(Boc)-OH; 사이클 18: Fmoc-Asn(Trt)-OH; 사이클 19: Fmoc-Val-OH; 사이클 20: Fmoc-Phe-OH; 사이클 21: Fmoc-Asp(OtBu)-OH; 사이클 22: Fmoc-Gln(Trt)-OH; 사이클 23: Fmoc-Gln(Trt)-OH; 사이클 24: Fmoc-His(Trt)-OH; 사이클 25: Fmoc-Ile-OH; 사이클 26: Fmoc-Lys(Boc)-OH; 사이클 27: Fmoc-Asp(OtBu)-OH; 사이클 28: Fmoc-Met-OH; 사이클 29: Fmoc-Ala-OH; 사이클 30: Fmoc-Ile-OH; 사이클 31: Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH; 사이클 32: Fmoc-Asp(OtBu)-OH; 사이클 33: Fmoc-Ser(tBu)-OH; 사이클 34: Fmoc-A6c-OH; 사이클 35: Fmoc-Phe-OH; 사이클 36: Fmoc-Gly-Thr(psiMe,Me,Pro)-OH; 사이클 37: Fmoc-Glu(OtBu)-OH; 사이클 38: Fmoc-Ala-OH; 및 사이클 39: Fmoc-Tyr(tBu)-OH. Fmoc-His(Trt)-OH의 커플링 프로토콜은 표준 프로토콜의 일부 변형 버전이다. 먼저 2분간 마이크로웨이브 파워를 끄고, 다시 마이크로웨이브 파워를 4분간 켰다(20와트; 최대 온도 50 ℃). 펩타이드 벡본이 완성되고 나면, 표준적인 피페리딘 처리를 실시하여 N-말단의 Fmoc기를 제거하였다. 그 후, 수지를 DMF로 잘 헹구고, 다시 DMF를 이동 용액으로 이용하여 50 ml 코니칼 튜브에 넣었다.
수지를 탈보호하고, 시약(5% TIS, 2% 물, 5% (w/v) 디티오트레이톨(DTT), 88% TFA) 5 ml을 처리하여 수지로부터 잘라낸 다음, 3.5시간 혼합하였다. 여과물을 45 ml의 차가운 무수 에틸 에테르 중에 모았다. 침전물을 10분간 3500 rpm으로 냉장 원심분리하여 펠렛화하였다. 에테르를 버리고, 펩타이드는 새로운 에테르에 다시 현탁하였다. 에테르 공정은 총 2회 수행하였다. 최종 에테르 세정 후, 펩타이드를 공기 건조시켜 남아있는 에테르를 제거하였다. 펩타이드 펠렛은 아세토니트릴(ACN) 8 ml에 재현탁한 다음, 탈이온수 8ml을 넣어, 완전히 용해시켰다. 펩타이드 용액을 질량 분광측정기로 분석하였다. 전기분무 이온화를 이용한 질량 분석을 통해, 원하는 선형 산물에 해당되는 질량 5011.7 달톤이 함유된 주 산물이 동정되었다. 조산물(약 500 mg)을, 250 x 4.6 mm C18 컬럼(Phenomenex; Torrance, CA, USA)에서 2-80% 아세토니트릴(0.1%TFA) 농도 구배를 30분간 수행하는, HPLC로 분석하였다. 분석용 HPLC에서 순도 34%가 확인되었다. 그 후, 조산물 펩타이드를 유속 10 ml/분으로 50분간 10-60% 아세토니트릴(0.1% TFA)을 이용하는 C18 역상 컬럼이 장착된 분취용 HPLC에서 정제하였다. 정제한 펩타이드는 동결건조하여, 15 mg으로 횟수하였다. 그 후, 선형 펩타이드에 N-프로필말레이미드(Pma)를 사용하여 유도체화함으로써, 시스테인 측쇄에 프로필 숙신이미드(Psu)를 생성시켰다. 정제된 선형 펩타이드를 암모늄 카보네이트로 pH 6.5로 조절한 물에 5 mg/ml로 넣었다. 5당량의 Pma를 30초간 일정한 속도로 교반하면서 첨가하였다. 그런 후, 유도체화된 펩타이드를 질량 분광측정기로 분석하였다. 전기분무 이온화를 사용한 질량 분석에서, 원하는 Psu 유도체화된 산물에 해당되는 질량 5150.7 달톤의 주 산물이 확인되었다. 이 산물을 상기와 동일한 농도 구배에서 분취용 HPLC로 다시 정제하였다. 정제된 산물을 HPLC로 순도(95.10%)를 분석하였고, 질량을 측정한 다음 (5150.9 Daltons), 동결건조하였다.
실시예
103: [
Orn
1
(N-C(O)-(
CH
2
)
12
-
CH
3
), A6c
7
]
hGIP
(1-42)-
OH
고상 펩타이드 합성을 이용하여, 리버르티 펩타이드 합성기(CEM; Matthews, NC, USA)에서 마이크로웨이브-조합 Fmoc 화학법을 이용하여 펩타이드를 0.1 mmole 수준으로 조립하였다. 프리-로드한 Fmoc-Gln(Trt)-Wang 수지(0.59 mmole/g; Novabiochem, San Diego, CA, USA)를 이용하여, C-말단 펩타이드를 제조하였다. 수지(0.17 g)를 15 ml의 디메틸포름아미드(DMF)와 함께 50 ml 코니칼 튜브에 넣고, 합성기에서 수지 위치에 주입하였다. 그 후, 수지는 자동 공정을 통해 반응 용기로 정량적으로 이동시켰다. 0.1 mmole 수준의 합성을 위한 표준적인 리버르티 합성 프로토콜을 사용하였다. 이 프로토콜에는, DMF 중의 0.1 M N-하이드록시벤조트리아졸(HOBT)이 함유된, 20% 피페리딘 7 ml을 먼저 처리하여, N-말단 Fmoc 모이어티를 탈보호화하는 단계가 포함되어 있다. 일차 탈보호 단계는 마이크로웨이브 파워(45 watts, 최대 온도: 75℃)와 질소 버블링(3초 실시/7초 휴식)을 이용하여 30초간 수행하였다. 그 후, 반응 용기를 배수시키고, 1차 처리와 동일하지만 3분간 실시하는 2차 피페리딘 처리를 수행하였다. 이후, 수지를 배수시키고, DMF로 여러번 완전히 세정하였다. DMF 중의 0.2 M 스톡 용액으로 준비한 보호된 아미노산 Fmoc-Thr(tBu)-OH를 첨가(2.5 ml, 5 eq.)한 다음, DMF 중의 0.45M (4.5 eq.) HBTU [2-(1H-벤조-트리아졸-1-일)-1,1,3,3-테트라메틸우로늄 헥사플루오로포스페이트] 1.0 ml을 첨가하였다. 이 후, NMP(N-메틸피롤리디논) 중의 2M (10 eq.) DIPEA(디이소프로필에틸아민) 0.5 ml을 첨가하였다. 20와트의 마이크로웨이브 파워를 이용하여, 최대 75℃에서 동일한 질소 버블링율로 5분간, 커플링 단계를 수행하였다.
1차 커플링 단계 다음에, 반응 용기를 배수시켜 버리고, 커플링 단계를 반복하였다. 사이클 1과 유사하게 사이클 2를 개시하였다. 아미노산 모두 유사하게 도입하였고, 전체 서열에 이중-커플링 전략을 적용하였다. 사이클 1-3, 19-20, 25-26, 및 30-39에는 커플링 단계 바로 다음 단계로 캡핑 공정을 포함시켰다. 캡핑은, NMP 중의 0.015 M HOBT가 포함된 0.5 M 무수 아세트산 7 ml을 2 M DIPEA 용액 2 ml과 함께 첨가하여, 다단계 마이크로웨이브 프로토콜(50와트의 파워로 30초간(최대 온도 65 ℃) -> 마이크로웨이브 파워를 끄고 30초 -> 제2 라운드: 마이크로웨이브 파워(50와트)로 30초간 -> 마이크로웨이브 파워 끈 상태로 다시 30초 수행)로 수행하여, 실시하였다. 그런 후, 수지를 배출시키고, DMF로 잘 헹구었다. 다음 아미노산(Advanced Chemtech, Louisville, KY, USA)을 사용하였다: 사이클 1: Fmoc-Thr(tBu)-OH; 사이클 2: Fmoc-Ile-OH; 사이클 3: Fmoc-Asn(Trt)-OH; 사이클 4: Fmoc-His(Trt)-OH; 사이클 5: Fmoc-Lys(Boc)-OH; 사이클 6: Fmoc-Trp(Boc)-OH; 사이클 7: Fmoc-Orn(Mtt)-OH; 사이클 8: Fmoc-Asn(Trt)-OH; 사이클 9: Fmoc-Lys(Boc)-OH; 사이클 10: Fmoc-Lys(Boc)-OH; 사이클 11: Fmoc-Gly-OH; 사이클 12: Fmoc-Lys(Boc)-OH; 사이클 13: Fmoc-Gln(Trt)-OH; 사이클 14: Fmoc-Ala-OH; 사이클 15: Fmoc-Leu-OH; 사이클 16: Fmoc-Leu-OH; 사이클 17: Fmoc-Trp(Boc)-OH; 사이클 18: Fmoc-Asn(Trt)-OH; 사이클 19: Fmoc-Val-OH; 사이클 20: Fmoc-Phe-OH; 사이클 21: Fmoc-Asp(OtBu)-OH; 사이클 22: Fmoc-Gln(Trt)-OH; 사이클 23: Fmoc-Gln(Trt)-OH; 사이클 24: Fmoc-His(Trt)-OH; 사이클 25: Fmoc-Ile-OH; 사이클 26: Fmoc-Lys(Boc)-OH; 사이클 27: Fmoc-Asp(OtBu)-OH; 사이클 28: Fmoc-Met-OH; 사이클 29: Fmoc-Ala-OH; 사이클 30: Fmoc-Ile-OH; 사이클 31: Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH; 사이클 32: Fmoc-Asp(OtBu)-OH; 사이클 33: Fmoc-Ser(tBu)-OH; 사이클 34: Fmoc-A6c-OH; 사이클 35: Fmoc-Phe-OH; 사이클 36: Fmoc-Gly-Thr(psiMe,Me,Pro)-OH; 사이클 37: Fmoc-Glu(OtBu)-OH; 사이클 38: Fmoc-Ala-OH; 및 사이클 39: Boc-Tyr(tBu)-OH. Fmoc-His(Trt)-OH의 커플링 프로토콜은 표준 프로토콜의 일부 변형 버전이다. 먼저 2분간 마이크로웨이브 파워를 끄고, 다시 마이크로웨이브 파워를 4분간 켰다(20와트; 최대 온도 50 ℃). 펩타이드 벡본이 완성되고 나면, 수지에, 12 ml의 1% 트리플루오로아세트산 (TFA) / 5% 트리이소프로필실란 (TIS)을 디클로로메탄(DCM) 중에서 5초간 N2 살포 및 10초간 비살포의 살포율로, 5분간 처리하였다. 수지를 다시 배수한 다음, 여기에 1% TFA / 5% TIS를 DCM 중의 용액으로 5분간 처리하였다. 이러한 과정을 총 7회 반복하여, 오르니틴 측쇄로부터 Mtt 모이어티를 사실상 제거하였다. 수지를 DCM으로 여러번 잘 헹군 다음, 오르니틴의 δN 상에 잔류하는 TFA 염을 중화하기 위해, 여기에 표준 피페리딘 처리를 처리하였다. DMF 중의 0.2 M 용액으로 준비한 미리스트산 (CH3-(CH2)12-COOH; Aldrich, St. Louis, MO, USA)을, 표준 아미노산 커플링 프로토콜을 이용하여 오르니틴 측쇄에 커플링하였다. 그 후, 수지를 DMF로 잘 헹구고, 다시 이동 용매로서 DMF를 이용하여 50 ml 코니칼 튜브로 다시 옮겼다.
수지를 탈보호하고, 시약(5% TIS, 2% 물, 5% (w/v) 디티오트리에이톨(DTT), 88% TFA) 5 ml을 처리하여 수지로부터 잘라낸 다음, 3.5시간 혼합하였다. 여과물을 45 ml의 차가운 무수 에틸 에테르 중에 모았다. 침전물을 10분간 3500 rpm으로 냉장 원심분리하여 펠렛화하였다. 에테르를 버리고, 펩타이드는 새로운 에테르에 다시 현탁하였다. 에테르 공정은 총 2회 수행하였다. 최종 에테르 세정 후, 펩타이드를 공기 건조시켜 남아있는 에테르를 제거하였다. 펩타이드 펠렛을 아세토니트릴(ACN) 8 ml에 재현탁한 다음, 탈이온수 8ml을 넣어, 완전히 용해시켰다. 펩타이드 용액을 질량 분광측정기로 분석하였다. 전기분무 이온화를 이용한 질량 분석을 통해, 원하는 선형 산물에 해당되는 질량 5205.1 달톤이 함유된 주 산물이 동정되었다. 조산물(약 ~500 mg)을, 250 x 4.6 mm C18 컬럼(Phenomenex; Torrance, CA, USA)에서 2-80% 아세토니트릴(0.1%TFA) 농도 구배를 30분간 수행하는, HPLC로 분석하였다. 분석용 HPLC에서 순도 50%가 확인되었다. 그 후, 펩타이드를 동일한 용출 농도 구배를 이용하여 C18 컬럼이 장착된 분취용 HPLC에서 정제하였다. 정제된 산물을 HPLC로 순도(96.10%)를 분석하였고, 질량을 측정한 다음 (5204.6 Dalton), 동결건조하였다. 동결건조 후, 정제 산물 6.2 mg을 수득하였으며, 이의 수율은 1.2%였다.
본원의 페길화된 GIP 화합물은, 실시예 15에서 사용된 N-프로필말레이미드 대신 출발물질로 PEG-말레이미드를 이용하여, 실시예 15의 화합물 합성에 기술된 방법으로 실질적으로 합성할 수 있다.
당해 기술 분야의 당업자라면 상기 실시예에 기술된 방법과 유사한 합성 방법을 사용하여 본 발명의 다른 펩타이드들도 제조할 수 있다. 본원에 예시된 화합물의 물리 데이타는 표 1에 나타낸다.
실시예 번호 | 분자량(예측치) | 분자량(ESI-MS) | 순도%(HPLC) |
1 | 4995.63 | 4996.5 | 95.67 |
2 | 4967.62 | 4968.2 | 97.88 |
3 | 4969.55 | 4971.3 | 99.90 |
4 | 4981.60 | 4982.9 | 99.90 |
5 | 5007.64 | 5007.5 | 96.32 |
6 | 4995.59 | 4994.8 | 96.17 |
7 | 4995.59 | 4996.6 | 95.84 |
8 | 4969.55 | 4968.9 | 93.98 |
9 | 4995.63 | 4996.8 | 93.30 |
10 | 5025.66 | 5027.0 | 9792 |
11 | 3556.04 | 3557.3 | 96.82 |
12 | 3543.99 | 3544.6 | 98.93 |
13 | 3543.99 | 3545.1 | 97.36 |
14 | 3574.06 | 3575.4 | 93.62 |
15 | 3530.00 | 3531.1 | 95.36 |
16 | 3517.95 | 3525.8 | 99.00 |
17 | 3544.03 | 3545.0 | 99.90 |
18 | 3516.02 | 3516.3 | 96.03 |
19 | 3544.03 | 3544.1 | 99.90 |
20 | 3517.95 | 3518.1 | 99.90 |
21 | 5005.60 | 5005.6 | 99.90 |
22 | 5037.67 | 5037.9 | 94.20 |
23 | 4993.62 | 4993.3 | 98.10 |
24 | 5019.63 | 5019.4 | 99.00 |
25 | 4975.58 | 4975.7 | 99.30 |
26 | 5003.59 | 5003.6 | 99.00 |
27 | 5003.59 | 5003.8 | 92.90 |
28 | 5003.59 | 5004.0 | 95.20 |
29 | 5015.64 | 5016.2 | 97.40 |
30 | 5005.60 | 5005.4 | 99.00 |
31 | 3539.98 | 3540.0 | 98.60 |
32 | 3525.95 | 3526.2 | 95.30 |
33 | 3525.99 | 3525.8 | 99.90 |
34 | 3551.99 | 3552.3 | 99.90 |
35 | 3523.93 | 3524.0 | 97.,70 |
36 | 3580.04 | 3580.0 | 99.90 |
37 | 5003.59 | 5003.5 | 99.90 |
38 | 3538.00 | 3538.3 | 99.99 |
39 | 3551.99 | 3552.1 | 97.40 |
40 | 5005.60 | 5005.5 | 99.00 |
41 | 4989.60 | 4989.6 | 99.00 |
42 | 4991.57 | 4991.9 | 99.00 |
43 | 5009.61 | 5009.5 | 99.00 |
44 | 4989.56 | 4989.5 | 99.80 |
45 | 4977.59 | 4977.4 | 99.00 |
46 | 3570.07 | 3569.8 | 99.00 |
47 | 3560.03 | 3557.8 | 99.00 |
48 | 5161.42 | 5161.3 | 99.90 |
49 | 5017.66 | 5018.0 | 99.90 |
50 | 5038.7 | 5038.6 | 99.90 |
51 | 5082.53 | 5082.5 | 99.90 |
52 | 3558.01 | 2559.8 | 99.00 |
53 | 5021.67 | 5021.5 | 94.70 |
54 | 5003.63 | 5004.0 | 99.00 |
55 | 4991.57 | 4991.3 | 99.00 |
56 | 5015.60 | 5015.6 | 98.70 |
57 | 4993.59 | 4993.8 | 96.50 |
58 | 4977.55 | 4977.8 | 99.00 |
59 | 4975.53 | 4975.0 | 99.00 |
60 | 5011.63 | 5011.5 | 99.00 |
61 | 5015.64 | 5015.9 | 99.00 |
62 | 4947.57 | 4948.1 | 99.90 |
63 | 4961.59 | 4961.1 | 99.90 |
64 | 4961.59 | 4960.6 | 99.90 |
65 | 4979.63 | 4980.0 | 99.00 |
66 | 5027.68 | 5027.3 | 99.90 |
67 | 4981.60 | 4981.3 | 99.70 |
68 | 4963.56 | 4963.9 | 99.90 |
69 | 5009.64 | 5009.8 | 99.90 |
70 | 4963.56 | 4963.3 | 99.90 |
71 | 5007.62 | 5007.2 | 98.60 |
72 | 4959.57 | 4959.9 | 99.90 |
73 | 5150.81 | 5150.9 | 95.10 |
74 | 4989.67 | 4989.8 | 98.80 |
75 | 4965.60 | 4966.0 | 99.99 |
76 | 4929.51 | 4929.6 | 99.00 |
77 | 4975.64 | 4975.6 | 97.12 |
78 | 5138.75 | 5139.0 | 95.60 |
79 | 5137.81 | 5138.1 | 99.90 |
80 | 5114.77 | 5114.3 | 99.90 |
81 | 5065.70 | 5065.6 | 98.90 |
82 | 5037.71 | 5037.9 | 99.90 |
83 | 4983.64 | 4983.8 | 99.90 |
84 | 4961.55 | 4961.5 | 99.90 |
85 | 5136.82 | 5136.6 | 99.90 |
86 | 5137.81 | 5137.6 | 99.90 |
87 | 4991.64 | 4991.7 | 98.80 |
88 | 4985.61 | 4985.2 | 99.90 |
89 | 5031.69 | 5031.8 | 99.90 |
90 | 5194.86 | 5194.3 | 99.90 |
91 | 4945.55 | 4945.0 | 99.90 |
92 | 3506.01 | 3505.9 | 99.90 |
93 | 5137.74 | 5137.5 | 99.90 |
94 | 5123.74 | 5124.0 | 98.30 |
95 | 5251.91 | 5252.0 | 98.60 |
96 | 3518.02 | 3518.2 | 99.90 |
97 | 3511.99 | 3512.0 | 98.80 |
98 | 3524.04 | 3523.8 | 99.90 |
99 | 5123.74 | 5123.5 | 99.90 |
100 | 5123.74 | 5123.5 | 97.90 |
101 | 4982.59 | 4982.0 | 99.90 |
102 | 4969.62 | 4969.4 | 99.90 |
103 | 5156.92 | 5156.7 | 95.50 |
104 | 5005.63 | 5005.8 | 97.19 |
105 | 5144.78 | 5144.8 | 95.62 |
106 | 5017.68 | 5018.4 | 96.00 |
107 | 5039.71 | 5040.4 | 99.90 |
108 | 3509.99 | 3509.8 | 99.90 |
109 | 3526.02 | 3525.7 | 99.00 |
110 | 3538.07 | 3538.1 | 99.99 |
111 | 3520.03 | 3519.9 | 99.99 |
112 | 3532.4 | 3532.0 | 99.90 |
113 | 5017.66 | 5018.0 | 99.90 |
117 | 5130.8 | 5130.8 | >99 |
118 | 5112.7 | 5112.9 | >99 |
119 | 5126.7 | 5126.5 | >99 |
121 | 3536.0 | 3536.4 | 97.0 |
122 | 3693.2 | 3693.5 | 98.2 |
123 | 5138.8 | 5138.5 | 99.9 |
기능 분석
A. 시험관내 hGIP 수용체 결합 분석
인간 재조합 GIP 수용체를 발현하는 CHO-K1 세포를 차가운 50 mM Tris-HCl 중에 브린크만 폴리트론(세팅 6, 15초)을 이용하여 균질화한 다음, 10분간 39,000g로 2회 원심분리한 다음 원심 분리 사이에 신선한 완충액에 재현탁하여, 시험관내 수용체 결합 분석용 막을 준비하였다. 분석을 위해, 세정한 막 조제물의 분액 25㎕을 50 mM Tris-HCl, 0.1 mg/ml 박시트락신 및 0.1% BSA 중에서 0.05 nM [125I]GIP (약 2200 Ci/mmol)과 인큐베이션하였다. 최종 분석 부피는 0.5 ml이었다. 브란델 여과 매니폴드를 이용하여 GF/C 필터(0.5% 폴리에틸렌이민에 미리 젖심)로 신속하게 여과하여, 인큐베이션을 종결지었다. 그 후, 각 튜브와 필터를 5 ml 차가운 완충액 분액으로 3번 헹구었다. 특이적인 결합은 총 방사성리간드 결합에서 1000 nM GIP의 존재 하에 결합된 것 제외한 값으로 하였다. 본원에 예시된 화합물들의 시험관내 hGIP 수용체 결합성 데이타는 표 2에 나타낸다.
B. 인간 및 랫 혈장 반감기 분석
GIP 펩타이드(50 ㎕ 1 mg/ml)를 450 ㎕ 혈장(인간 또는 랫)에 넣고 간단하게 볼텍싱한 다음 37℃에서 인큐베이션하였다. 다양한 시간대, 예컨대 0, 1, 2, 3, 4, 8, 24, 32, 48, 56, 72 시간에, 50 ㎕를 취하고, 5 ㎕ 포름산 및 150 ㎕ 아세토니트릴과 초원심분리관에서 혼합하고, 볼텍싱한 다음 10K rpm으로 10분간 원심분리하였다. 상층액을 주입 바이얼로 옮기고, LC-MS로 분석하였다. LC-MS 시스템은 API400 질량 분광측정기와 ESI 프로브로 구성되어 있다. 파지티브 이온 모드 및 풀 스크린 검출을 이용하였다. HPLC 분리를, Luna 3μ C8 (2), 2 x 30 mm 컬럼 상에서 유속 0.3 ml/분으로 10분간 90% A에서 90% B의 농도 구배를 이용하여 수행하였다. 완충액 A는 수 중의 1% 포름산이고, 완충액 B는 1% 포름산 아세토니트릴이다. 본원에 예시된 화합물의 인간 및 랫 혈장 반감기는 표 2에 나타낸다.
실시예 번호 | Ki (nM) | 인간 혈장 T½(hr) | 랫 혈장 T½(hr) |
1 | 0.801.20 | >48 | 3.9 |
2 | 1.202.66 | 9.4/7.6 | 4.1/5.6 |
3 | 2.660.75 | >48 | 5.5 |
4 | 0.754.08 | >48 | 4.8 |
5 | 2.26 | >48 | 6.1 |
6 | 0.41 | >48 | 8.6 |
7 | 1.65 | 37.1 | 5.3 |
8 | 4.98 | >48 | 4.5 |
9 | 16.25 | >48 | 9.2 |
10 | 80.07 | >48 | 4.0 |
11 | 2.05 | 44.4 | >48 |
12 | 0.27 | 20.5 | >48 |
13 | 0.98 | 35.4 | >48 |
14 | 106.63 | 34.8 | 48 |
15 | 3.33 | 28.6 | 46.5 |
16 | 0.53 | 43.9 | >48 |
17 | 15.93 | 17.4 | 55.0 |
18 | 5.38 | 11.3 | 44.4 |
19 | 0.37 | 27.2 | >48 |
20 | 1.84 | 25.4 | 42 |
21 | 0.30 | >48 | 12.3 |
22 | 6.96 | >48 | 14.2 |
23 | 0.87 | >48 | 6.7 |
24 | 2.06 | >48 | 24.8 |
25 | 1.33 | >48 | 8.4 |
26 | 2.54 | N/A | N/A |
27 | 120.95 | >48 | 9.3 |
28 | 1.09 | >48 | 11.6 |
29 | 1.17 | >48 | 7.3 |
30 | 1.22 | >48 | 13.4 |
31 | 1.04 | 36.5 | 31.4 |
32 | 4.90 | >48 | 28.3 |
33 | 1.39 | >48 | 34 |
34 | 25.80 | >48 | 23 |
35 | 2.32 | >48 | 39.4 |
36 | 46.97 | 23.7 | 29.2 |
37 | 1.06 | >48 | 14.0 |
38 | 0.73 | 49.1 | >54 |
39 | 1.19 | 42.3 | 43.3 |
40 | 15.89 | 7.7 | 4.9 |
41 | 0.73 | 15.9 | 13.3 |
42 | 0.07 | 10.6 | 6.2 |
43 | 0.30 | 8.8 | 7.7 |
44 | 0.63 | 9.5 | 7.5 |
45 | 0.29 | 18.2 | 11.6 |
46 | 0.09 | 12.2 | >54 |
47 | 0.33 | 45.3 | 30.8 |
48 | 0.15 | >56 | >54 |
49 | 0.09 | >56 | 45.0 |
50 | 0.16 | 48.1 | >54 |
51 | 0.83 | 33.8 | 12.7 |
52 | 0.03 | 14.0 | 28.2 |
53 | 0.08 | 33.3 | 51.7 |
54 | 0.43 | >56 | 44.1 |
55 | 0.45 | 8.8 | 11.7 |
56 | 34.38 | 16.0 | 9.2 |
57 | 0.05 | 30.5 | 13.8 |
58 | 0.69 | 37.6 | 16.7 |
59 | 0.22 | 24.0 | 13.1 |
60 | 0.05 | 26.0 | 10.5 |
61 | 0.18 | >48 | 45.3 |
62 | 666.95 | 11.4 | 1.4 |
63 | 330.11 | 14.2 | 1.4 |
64 | 727.37 | 41.3 | 47.5 |
65 | N/A | 14.3 | 1.5 |
66 | N/A | 19.1 | 8.8 |
67 | N/A | >33 | 1.6 |
68 | N/A | >48 | 1.9 |
69 | N/A | 36.9 | 1.8 |
70 | N/A | >33 | 1.5 |
71 | N/A | >31 | 4.8 |
72 | N/A | 10.7 | 0.45 |
73 | 63.57 | N/A | N/A |
74 | N/A | 16.3 | 1.3 |
75 | N/A | 26.1 | 1.9 |
76 | N/A | 55.9 | 1.0 |
77 | N/A | 43.3 | 1.5 |
78 | 15.97 | 10.1 | 11.2 |
79 | 13.78 | N/A | 14.3 |
80 | 5.05 | >54 | 5.5 |
81 | 635.48 | 8.2 | 6.1 |
82 | 503.00 | 9.7 | 10.2 |
83 | N/A | 32.4 | 1.1 |
84 | 909.50 | 3.3 | 1.9 |
85 | 288.33 | 7.3 | 3.5 |
86 | 3255.54 | 4.2 | 7.0 |
87 | N/A | 38.7 | 3.4 |
88 | N/A | >48 | 4.4 |
89 | 753.50 | >48 | 11.8 |
90 | 75.78 | 11.3 | 4.8 |
91 | 214.00 | 13.4 | 1.0 |
92 | 86.79 | 12.0 | 1.6 |
93 | 0.9435.37 | N/A | N/A |
94 | 2.59 | N/A | N/A |
95 | N/A | N/A | N/A |
96 | 870.94 | N/A | N/A |
97 | 181.00 | N/A | N/A |
98 | 65.85 | N/A | N/A |
99 | 1.51 | N/A | N/A |
100 | 22.68 | N/A | N/A |
101 | 2.25 | 47.5 | 13.4 |
102 | 647.50 | 54.1 | 1.7 |
103 | 21.47 | 6.8 | >72 |
104 | 0.59 | 20.2 | 14.8 |
105 | 0.56 | 19.1 | 6.9 |
106 | 0.36 | >55 | 9.2 |
107 | 6.67 | N/A | N/A |
108 | 0.07 | 46.2 | 45.6 |
109 | 333.46 | 27.2 | 47.8 |
110 | 216.24 | 13.7 | 25.8 |
111 | N/A | >54 | >54 |
112 | 34.12 | 59.7 | >72 |
113 | 0.19 | 61.9 | 27.0 |
117 | 0.97 | 25.2 | 10.5 |
118 | 0.87 | >42 | 11.2 |
119 | 0.66 | 35.7 | 15.4 |
121 | 0.46 | N/A | N/A |
122 | 0.87 | N/A | N/A |
123 | 0.55 | N/A | N/A |
표 2에 기재된 데이타 비교에서, PCT 공개 WO 00/58360에 기재된 화합물 [Pro3]hGIP(1-42)-OH에 대한 시험관내 hGIP 수용체 결합 데이타 및 랫 혈장 반감기 데이타를 전술한 동일한 실험 조건에서 측정하여 각각 170.8 nM, 10.8시간 및 0.8시간으로 측정되었다.
C. 사이클릭 AMP 자극 측정
인간 재조합 GIP 수용체를 발현하는 1 x 105 개의 CHO-K1 또는 RIN-5F 인슐린종(insulinoma) 세포를 24웰 세포 배양 플레이트(Corning Incorporate, Corning, NY, USA)에 접종하여 밤새 배양하였다. 분석을 위해, 세포를 500 ㎕의 행크스 밸런싱 염 용액(Sigma, St. Louis, MO, USA)에서 pH 7.3으로 조절한 0.55 mM IBMX (Sigma, St. Louis, MO, USA)와 함께 전배양하였다. 그 후, GIP 또는 그 유사체를 100 nM 농도로 첨가하였다. 37℃에서 30분간 인큐베이션한 후, 플레이트를 얼음 위에 두고, 차가운 무수 에탄올 500 ㎕를 첨가하여 반응을 정지시켰다. 웰내 내용물을 모아 20분간 4℃에서 2,700 g로 스핀하여, 세포 찌꺼기를 제거하였다. 상층액 중의 cAMP 수준은 방사면역분석(New England Nuclear, Boston, MA, USA)으로 측정하였다.
D. 정상 랫에서의 생체내 인슐린 분비 측정
체중 약 275-300 g의 수컷 스프래그 다우리 랫을 실험 대상으로 사용하였다. 처리 하루 전에, 클로로하이드레이트 하에 경정맥을 통해 우측 동맥 캐뉼러를 이식하였다. 각 캐뉼러에 100 u/ml 헤파린 염수를 충전하고, 봉하였다. 화합물 또는 비히클(염수/0.25% BSA)를 투약하기 약 18시간 전에 랫에 금식시켰다. 실험 당일, 화합물 분액을 해동시켜 실온으로 만든 후 잘 혼합하였다. 화합물의 용액 석출 사인을 모두 조심스럽게 체크하였다. 화합물/포도당 주사하기 10분 전에, 혈액 샘플 500 ㎕를 취하여, 동일 부피의 헤파린 처리한 염수와 교환하였다(10 u/ml). 0시간대에, 500 ㎕ 혈액 샘플을 캐뉼러를 통해 취하였다. 그 후, 비히클 또는 적정 용량의 화합물을 캐뉼러에 주입하여, 포도당(1 g/kg) 또는 비피클 용액으로 밀어 넣었다. 최종적으로, 헤파린 처리한 염수(10 u/ml) 500 ㎕를 사용하여 남아있는 포도당을 캐뉼러를 통해 밀어 넣었다. 다시 500 ㎕의 혈액 샘플을 포도당 부하 후 2.5, 5, 10 및 20분 후에 취하고, 바로 즉시 헤파린 처리한 염수(10 u/ml) 500 ㎕를 캐뉼러를 통해 IV 주사하였다. 혈액 샘플을 원심 분리하여 혈장을 모우고, 인슐린 함량에 대해 분석할 때까지 -20℃에 저장하였다. 실시예 105, 106, 118 및 119의 화합물의 생체내 효과를 나타내는 총 인슐린 분비 값을 표 3에 요약 개시한다.
AUC | |
비히클/비히클 | 20.54 |
비히클/포도당 | 4.11 |
실시예 105 | 114.70 |
실시예 106 | 161.73 |
실시예 118 | 88.22 |
실시예 119 | 167.48 |
투약
본 발명의 펩타이드는 약학적으로 허용가능한 염 형태로 제공될 수 있다. 그러한 염의 예로는, 유기산(예, 아세트산, 락트산, 말레산, 시트르산, 말산, 아스코르브산, 숙신산, 벤조산, 메탄설폰산, 톨루엔설폰산 또는 파모산), 무기산(예, 염산, 황산, 또는 인산) 및 폴리머산(예, 탄닌산, 카르복시메틸 셀룰로스, 폴리락트산, 또는 폴리락트산-글리콜산의 공중합체)과 형성된 염이 있으나, 이로 한정되는 것은 아니다. 본 발명의 펩타이드 염을 제조하는 전형적인 방법은 당업계에 잘 알려져 있으며, 표준적인 염 교환 방법에 의해 달성될 수 있다. 따라서, 본 발명의 펩타이드의 TFA 염(분취용 HPLC를 이용하고, TFA가 함유된 완충액에 의한 용출로, 펩타이드 정제하여 수득되는 TFA 염)은, 0.25 N 아세트산 수용액 소량에 펩타이드를 용해시킴으로써, 아세테이트 염과 같은 다른 염으로 변환시킬 수 있다. 수득되는 용액은 세미-분취용 HPLC 컬럼(Zorbax®, 300 SB, C-8)에 적용한다. 컬럼은, (1) 0.1 N 암모늄 아세테이트 수용액으로 0.5시간; (2) 0.25 N 아세트산 수용액으로 0.5시간; 및 (3) 유속 4 ml/min로 선형 농도 구배(용액 B를 30분간 20%에서 100%로 농도 구배(용액 A는 0.25 N 아세트산 수용액이고, 용액 B는 아세토니트릴/물, 80:20 중의 0.25 N 아세트산 수용액임)로 용출시킨다. 펩타이드가 함유된 분획들을 모아 동결건조하여 건조하였다.
본 발명의 조성물에서 활성 성분의 투여량은 다양할 수 있지만, 활성 성분의 양은 적합한 투약 형태를 수득할 수 있어야 한다. 선택되는 투여량은 원하는 원하는 치료 효과, 투여 경로 및 치료 기간에 따라 결정된다. 대게, 본 발명의 활성에 있어 유효량은 1x10-7 내지 200 mg/kg/day, 바람직하기로는 1x10-4 내지 100 mg/kg/day이며, 이는 단일 투약(single dose)으로서 투여하거나 또는 다중 투약(multiple doses)으로 분할하여 투여할 수 있다.
본 발명의 화합물은 경구, 비경구(예, 근육내, 복막내, 정맥내 또는 피하내 주입 또는 이식), 비내, 질, 직장, 설하 또는 국소 투여 경로에 의해 투여될 수 있으며, 각 투여 경로에 적합한 투약 형태를 제공하기 위해 약제학적으로 허용가능한 담체와 함께 제형화될 수 있다.
경구 투여를 위한 고형의 투약 형태로는, 캡슐제, 정제, 환제(pills), 산제 및 과립제를 포함한다. 상기 고형의 투약 형태에서, 활성 화합물은 하나 이상의 약학적으로 허용가능한 불활성 담체, 예컨대 자당, 유당 또는 전분과 혼합된다. 상기 투약 형태는 또한 통상 실시되는 바와 같이, 상기한 불활성 희석제 이외의 부가적인 물질, 예컨대 마그네슘 스테아레이트와 같은 윤활제를 포함할 수 있다. 캡슐제, 정제 및 환제의 경우, 투약 형태는 또한 완충제를 포함할 수도 있다. 정제와 환제는 부가적으로 장내 코팅형태(entteric coating)로 제조될 수 있다
경구 투여를 위한 액상 투약 형태는, 물과 같이 당해분야에서 일반적으로 사용되는 불활성의 희석제를 함유하는, 약학적으로 허용가능한 유제, 액제, 현탁제, 시럽제, 엘릭실제를 포함하나, 이로 한정되는 것은 아니다. 이러한 불활성의 희석제 이외에도, 조성물은 또한 습윤제, 유화제, 현탁제, 감미제, 향미제 및 향료와 같은 보강제(adjuvant)를 더 포함할 수 있다.
본 발명의 비경구 투여용 조제물은, 무균 수용액 또는 비수성 용액, 현탁제 또는 유제 등을 포함하지만, 이들로 한정되는 것은 아니다. 비수성 용액 또는 비히클의 예로는, 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브 오일 및 옥수수 오일과 같은 식물성 오일, 젤라틴 및 에틸 올레이트와 같은 주사가능한 유기 에스테르를 포함한다. 이러한 투약 형태는 또한 보존제, 습윤제, 유화제 및 분산제와 같은 보강제를 포함할 수도 있다. 이는, 예컨대 박테리아 체류 필터를 통한 여과, 조성물내 멸균제 첨가, 조성물에 방사선 조사 또는 조성물의 열처리에 의해 멸균시킬 수도 있다. 또한, 이는 사용하기 바로 전에 멸균수 또는 주입가능한 기타 멸균 매질에 용해할 수 있는 고형의 멸균 조성물의 형태로 제조될 수 있다.
직장 또는 질 투여용 조성물은 바람직하기로는 활성 성분과 더불어 코코아 버터나 좌제 왁스와 같은 부형제를 포함할 수도 있는 좌제이다.
비내 또는 설하 투여용 조성물은 또는 당해분야에 잘 알려진 표준적인 부형제가 부가된 형태로 제조된다.
또한, 본 발명의 화합물은 하기 특허 및 특허 출원에 개시된 바와 같이 서방형 조성물 형태로 투여될 수 있다. 미국 특허 제 5,672,659호에는, 생활성제와 폴리에스테르로 구성된 서방형 조성물이 개시되어 있다. 미국 특허 제 5,595,760호에는 생활성제로 구성된 젤 형태의 서방형 조성물이 개시되어 있다. 미국 특허 제 5,821,221호에는 생활성제 및 키토산으로 구성된 폴리머성 서방형 조성물이 개시되어 있다. 미국 특허 제 5,916,883호에는 생활성제 및 사이클로덱스트린으로 구성된 서방형 조성물이 개시되어 있다. PCT 공개 WO99/38536에는 생활성제의 흡수성 서방형 조성물이 개시되어 있다. PCT 공개 WO00/04916에는 수중유 공정에서 펩타이드와 같은 치료제를 포함하는 미세입자를 제조하는 방법이 개시되어 있다. PCT 공개 WO00/09166에는 펩타이드와 인산화된 폴리머와 같은 치료제를 포함하는 복합체가 개시되어 있다. PCT 공개 WO00/25826에는 비-중합성 락톤을 가진 펩타이드 및 폴리머와 같은 치료제를 포함하는 복합체가 개시되어 있다.
다르게 정의된 경우를 제외하고는, 본원에 사용된 모든 기술 용어와 과학 용어는 본 발명이 속하는 기술 분야의 당업자에게 일반적으로 이해되는 바와 동일한 의미를 가진다. 또한, 본원에 언급된 모든 공개문헌, 특허 출원, 특허 및 그외 참고문헌들은 그 전체가 원용에 의해 본 명세서에 포함된다.
SEQUENCE LISTING
<110> IPSEN PHARMA S.A.S.
DONG, Zheng Xin
<120> Analogues of Glucose-Dependent Insulinotropic Polypeptide
<130> 177P2/PCT2
<150> 61/188,191
<151> 2008-08-07
<150> 61/200,629
<151> 2008-12-02
<160> 123
<170> PatentIn version 3.5
<210> 1
<211> 42
<212> PRT
<213> Homo sapiens
<400> 1
Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 2
<211> 30
<212> PRT
<213> Homo sapiens
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 2
Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 3
<211> 42
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid
<400> 3
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 4
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 4
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 5
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 5
Tyr Xaa Glu Gly Thr Phe Ile Ser Xaa Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 6
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 6
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 7
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 7
Tyr Xaa Glu Gly Xaa Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 8
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 8
Tyr Xaa Glu Gly Xaa Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 9
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 9
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 10
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 10
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Xaa Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 11
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 11
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Xaa Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 12
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 12
Tyr Xaa Glu Gly Thr Phe Ile Xaa Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 13
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 13
Tyr Xaa Glu Xaa Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 14
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 14
Tyr Xaa Glu Gly Xaa Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 15
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 15
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 16
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 16
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Xaa Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 17
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 17
Tyr Xaa Glu Xaa Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 18
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 18
Tyr Xaa Glu Gly Xaa Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 19
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 19
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 20
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 20
Tyr Xaa Glu Gly Thr Phe Ile Xaa Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 21
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 21
Tyr Xaa Glu Gly Thr Phe Ile Ser Xaa Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 22
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 22
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 23
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 23
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Xaa Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 24
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 24
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 25
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 25
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Xaa Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 26
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (41)..(41)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 26
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Xaa Gln
35 40
<210> 27
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MISC_FEATURE
<222> (31)..(31)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 27
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Xaa Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 28
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MISC_FEATURE
<222> (41)..(41)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 28
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Xaa Gln
35 40
<210> 29
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MISC_FEATURE
<222> (26)..(26)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 29
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Xaa Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 30
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 30
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Xaa Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 31
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MISC_FEATURE
<222> (40)..(40)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 31
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Xaa Thr Gln
35 40
<210> 32
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MISC_FEATURE
<222> (41)..(41)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 32
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Xaa Gln
35 40
<210> 33
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MISC_FEATURE
<222> (28)..(28)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 33
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Xaa Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 34
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 34
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 35
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 35
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 36
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 36
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 37
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 37
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 38
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 38
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 39
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 39
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 40
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 40
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Xaa His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 41
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 41
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 42
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 42
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 43
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 43
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 44
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 44
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 45
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 45
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 46
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 46
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 47
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 47
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 48
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 48
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 49
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 49
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 50
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 50
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 51
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 51
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 52
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 52
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 53
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 53
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 54
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 54
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 55
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 55
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 56
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 56
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 57
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 57
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 58
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 58
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 59
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 59
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 60
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 60
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 61
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 61
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 62
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 62
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 63
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 63
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 64
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 64
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 65
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 65
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 66
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = homoproline (hPro)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 66
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 67
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = 3,4-dehydroproline (Dhp)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 67
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 68
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = homoproline (hPro)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 68
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 69
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = tetrahydroisoquinoline-3-carboxylic acid (Tic)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 69
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 70
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = 4-hydroxyproline (4Hyp)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 70
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 71
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = 4-hydroxyproline (4Hyp)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 71
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 72
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = tetrahydroisoquinoline-3-carboxylic acid (Tic)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 72
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 73
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = 3-hydroxyproline (3Hyp)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 73
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 74
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = tetrahydroisoquinoline-3-carboxylic acid (Tic)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 74
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 75
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = homoproline (hPro)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 75
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 76
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (41)..(41)
<223> modified with N-propylsuccinimide (Psu)
<400> 76
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Cys Gln
35 40
<210> 77
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = homoproline (hPro)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 77
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 78
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 78
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 79
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 79
Tyr Ala Pro Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 80
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 80
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 81
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (40)..(40)
<223> modified with N-propylsuccinimide (Psu)
<400> 81
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Cys Thr Gln
35 40
<210> 82
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (39)..(39)
<223> modified with N-propylsuccinimide (Psu)
<400> 82
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Cys Ile Thr Gln
35 40
<210> 83
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (38)..(38)
<223> modified with N-propylsuccinimide (Psu)
<400> 83
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys Cys Asn Ile Thr Gln
35 40
<210> 84
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (36)..(36)
<223> modified with N-propylsuccinimide (Psu)
<400> 84
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Cys Lys His Asn Ile Thr Gln
35 40
<210> 85
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = tetrahydroisoquinoline-3-carboxylic acid (Tic)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 85
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 86
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = homoproline (hPro)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 86
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 87
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = 4-hydroxyproline (4Hyp)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 87
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 88
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (35)..(35)
<223> modified with N-propylsuccinimide (Psu)
<400> 88
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Cys Trp Lys His Asn Ile Thr Gln
35 40
<210> 89
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (34)..(34)
<223> modified with N-propylsuccinimide (Psu)
<400> 89
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Cys Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 90
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = 4-hydroxyproline (4Hyp)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 90
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 91
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = 4-hydroxyproline (4Hyp)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 91
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 92
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = tetrahydroisoquinoline-3-carboxylic acid (Tic)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 92
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 93
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (31)..(31)
<223> modified with N-propylsuccinimide (Psu)
<400> 93
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Cys Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 94
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 94
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 95
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 95
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 96
<211> 43
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 96
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln Gln
35 40
<210> 97
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (32)..(32)
<223> modified with N-propylsuccinimide (Psu)
<400> 97
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Cys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 98
<211> 43
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (43)..(43)
<223> modified with N-propylsuccinimide (Psu)
<400> 98
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln Cys
35 40
<210> 99
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 99
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 100
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 100
Tyr Ala Pro Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 101
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 101
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 102
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (33)..(33)
<223> modified with N-propylsuccinimide (Psu)
<400> 102
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Cys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 103
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (37)..(37)
<223> modified with N-propylsuccinimide (Psu)
<400> 103
Tyr Xaa Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Cys His Asn Ile Thr Gln
35 40
<210> 104
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa = 3-(4-hydroxyphenyl)propionic acid (4Hppa)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 104
Xaa Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 105
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 105
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 106
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa = ornithine (Orn)
<220>
<221> MOD_RES
<222> (1)..(1)
<223> modified with (N-C(O)-(CH2)12-CH3)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 106
Xaa Ala Glu Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 107
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 107
Tyr Xaa Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 108
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 108
Tyr Xaa Pro Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 109
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 109
Tyr Xaa Pro Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 110
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 110
Tyr Xaa Pro Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 111
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION
<400> 111
Tyr Xaa Pro Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys
20 25 30
<210> 112
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa = N-methyl-tyrosine (NMe-Tyr)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 112
Xaa Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 113
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<220>
<221> MISC_FEATURE
<222> (41)..(41)
<223> Xaa = 1-amino-1-cyclohexanecarboxylic acid (A6c)
<400> 113
Tyr Gly Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Xaa Gln
35 40
<210> 114
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (40)..(40)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 114
Tyr Gly Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Xaa Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Xaa Thr Gln
35 40
<210> 115
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (41)..(41)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 115
Tyr Gly Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Xaa Gln
35 40
<210> 116
<211> 43
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 116
Tyr Gly Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln His
35 40
<210> 117
<211> 43
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = norleucine (Nle)
<400> 117
Tyr Gly Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln His
35 40
<210> 118
<211> 43
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = 1-amino-1-cyclopentanecarboxylic acid (A5c)
<400> 118
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Xaa Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln His
35 40
<210> 119
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<220>
<221> MOD_RES
<222> (42)..(42)
<223> AMIDATION
<400> 119
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Xaa Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 120
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<400> 120
Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 121
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = alpha-aminoisobutyric acid (Aib)
<400> 121
Tyr Ala Xaa Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 122
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<400> 122
Tyr Ser Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
<210> 123
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic analog of glucose-dependent insulinotropic polypeptide
(GIP)
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = alpha-aminobutyric acid (Abu)
<400> 123
Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys
1 5 10 15
Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys
20 25 30
Lys Asn Asp Trp Lys His Asn Ile Thr Gln
35 40
Claims (42)
- 식 (I)의 화합물 또는 그의 약학적으로 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-A38-A39-A40-A41-A42-A43-R1 ,
(I)
상기 식 (I)에서,
A1은 Tyr이고;
A2는 Ala, A5c, A6c, Aib, D-Ala, 또는 Gly이고;
A3은 Glu, 3Hyp, 4Hyp, Pro, hPro, 또는 Tic이고;
A4는 Gly이고;
A5는 Thr이고;
A6은 Phe이고;
A7은 Ile이고;
A8은 Ser이고;
A9는 Asp이고;
A10은 Tyr이고;
A11은 A5c, A6c, 또는 Aib이고;
A12은 Ile이고;
A13은 Ala이고;
A14는 Met, A5c, A6c, 또는 Nle이고;
A15는 Asp이고;
A16은 Lys이고;
A17은 Ile이고;
A18은 His이고;
A19는 Gln이고;
A20은 Gln이고;
A21은 Asp이고;
A22는 Phe이고;
A23은 Val이고;
A24는 Asn이고;
A25는 Trp이고;
A26은 Leu이고;
A27은 Leu이고;
A28은 Ala이고;
A29는 Gln이고;
A30은 Lys이고;
A31은 Gly, His, 또는 결손되고;
A32는 Lys, 또는 결손되고;
A33은 Lys, 또는 결손되고;
A34는 Asn, 또는 결손되고;
A35는 Asp, 또는 결손되고;
A36은 Trp, 또는 결손되고;
A37은 Lys, 또는 결손되고;
A38은 His, 또는 결손되고;
A39는 Asn, 또는 결손되고;
A40은 Ile, A5c, 또는 결손되고;
A41은 Thr, A5c, A6c, 또는 결손되고;
A42는 Gln, 또는 결손되고;
A43은 His, 또는 결손되고,
R1은 OH, NH2, (C1-C30)알콕시, 또는 NH-X2-CH2-Z0이되, X2는 (C0-C30) 탄화수소 모이어티이고 Z0은 H, OH, CO2H, 또는 CONH2이고;
각각의 R2 및 R3는 독립적으로 H, (C1-C30)알킬, (C1-C30)헤테로알킬, (C1-C30)아실, (C2-C30)알케닐, (C2-C30)알키닐, 아릴(C1-C30)알킬, 및 아릴(C1-C30)아실, 치환된 (C1-C30)알킬, 치환된 (C1-C30)헤테로알킬, 치환된 (C1-C30)아실, 치환된 (C2-C30)알케닐, 치환된 (C2-C30)알키닐, 치환된 아릴(C1-C30)알킬, 및 치환된 아릴(C1-C30)아실로 이루어진 군으로부터 선택되되, R2가 (C1-C30)아실, 또는 아릴(C1-C30)아실, 치환된 (C1-C30)아실, 또는 치환된 아릴(C1-C30)아실인 경우에는, R3는 H, (C1-C30)알킬, (C1-C30)헤테로알킬, (C2-C30)알케닐, (C2-C30)알키닐, 또는 아릴(C1-C30)알킬, 치환된 (C1-C30)알킬, 치환된 (C1-C30)헤테로알킬, 치환된 (C2-C30)알케닐, 치환된 (C2-C30)알키닐, 또는 치환된 아릴(C1-C30)알킬이고;
또한, 상기 화합물의 2 또는 3번 위치에서 오직 하나의 아미노산이 치환되거나 변형된 것이며;
상기 화합물은, 4-42번 위치 중 임의의 위치에, 천연 GIP의 대응되는 위치의 아미노산 잔기가 아닌, 하나 이상의 부가적인 아미노산 치환 또는 변형을 포함한다. - 제1항에 있어서, 상기 화합물은 다음과 같이 정의되는 화합물 또는 그의 약학적으로 허용가능한 염:
A1 는 Tyr;
A2 는 Ala, Aib, D-Ala, 또는 Gly;
A3 는 Glu, 4Hyp, Pro, hPro, 또는 Tic;
A4 는 Gly;
A5 는 Thr;
A6 는 Phe;
A7 는 Ile;
A8 는 Ser;
A9 는 Asp;
A10 는 Tyr;
A11 는 A5c, A6c, 또는 Aib;
A12 는 Ile;
A13 는 Ala;
A14 는 Met, A5c, A6c, 또는 Nle;
A15 는 Asp;
A16 는 Lys;
A17 는 Ile;
A18 는 His;
A19 는 Gln;
A20 는 Gln;
A21 는 Asp;
A22 는 Phe;
A23 는 Val;
A24 는 Asn;
A25 는 Trp;
A26 는 Leu;
A27 는 Leu;
A28 는 Ala;
A29 는 Gln;
A30 는 Lys;
A31 는 Gly, His 또는 결손되고;
A32 는 Lys 또는 결손되고;
A33 는 Lys 또는 결손되고;
A34 는 Asn 또는 결손되고;
A35 는 Asp 또는 결손되고;
A36 는 Trp 또는 결손되고;
A37 는 Lys 또는 결손되고;
A38 는 His 또는 결손되고;
A39 는 Asn 또는 결손되고;
A40 는 Ile, A5c 또는 결손되고;
A41 는 Thr, A5c 또는 결손되고;
A42 는 Gln 또는 결손되고;
A43 는 His 또는 결손되고;
R1 는 OH, NH2;
각각의 R2 또는 R3는 H이며;
A7, A11, A13 또는 A14 위치 중 하나 이상은 천연 GIP의 대응 위치의 아미노산 잔기가 아니다. - 제1항에 있어서, 상기 화합물이
(Aib2, 11, Nle14)hGIP(1-30)-NH2 (서열번호 36);
(Aib2, 11, Nle14)hGIP(1-42)-OH (서열번호 48);
(Aib2, A5c11)hGIP(1-30)-NH2 (서열번호 49);
(Aib2, A5c11, A6c14)hGIP(1-30)-NH2 (서열번호 51);
(Aib2, A5c11, Nle14)hGIP(1-30)-NH2 (서열번호 53);
(Aib2, A5c11)hGIP(1-42)-OH (서열번호 56);
(Aib2, A5c11, Nle14)hGIP(1-42)-OH (서열번호 57);
(Aib2, A5c11, A6c14)hGIP(1-42)-OH (서열번호 64);
(hPro3, A5c11)hGIP(1-42)-OH (서열번호 77);
(Pro3, A5c11)hGIP(1-42)-OH (서열번호 80);
(Tic3, A5c11)hGIP(1-42)-OH (서열번호 85);
(hPro3, A5c11, A6c14)hGIP(1-42)-OH (서열번호 86);
(4Hyp3, A5c11)hGIP(1-42)-OH (서열번호 90);
(4Hyp3, A5c11, A6c14)hGIP(1-42)-OH (서열번호 91);
(Tic3, A5c11, A6c14)hGIP(1-42)-OH (서열번호 92);
(Pro3, A5c11, Nle14)hGIP(1-30)-OH (서열번호 95);
(Pro3, A5c11, A6c14)hGIP(1-30)-NH2 (서열번호 99);
(Pro3, A5c11)hGIP(1-30)-NH2 (서열번호 101);
(Pro3, A5c11, A6c14)hGIP(1-42)-OH (서열번호 105);
(D-Ala2, A5c11, 40)hGIP(1-42)-OH;
(D-Ala2, A5c11, His43)hGIP(1-43)-OH;
(D-Ala2, A5c11, 41)hGIP(1-42)-OH;
(D-Ala2, A6c11, 14, 41)hGIP(1-42)-OH;
(Gly2, A5c11, His43)hGIP(1-43)-OH (서열번호 116);
(Gly2, A5c11, Nle14, His43)hGIP(1-43)-OH (서열번호 117);
(D-Ala2, A5c11, Nle14, His43)hGIP(1-43)-OH;
(D-Ala2, A5c11, 14, His43)hGIP(1-43)-OH;
(D-Ala2, A5c11, 14)hGIP(1-30)-NH2;
(D-Ala2, A5c11, His31)hGIP(1-31)-NH2; 또는
(Aib2, A5c11, 14, His43)hGIP(1-43)-OH (서열번호 118)이거나,
또는 그의 약학적으로 허용가능한 염. - 제2항에 있어서, 상기 화합물은
(Aib2, 11, Nle14)hGIP(1-30)-NH2 (서열번호 36);
(Aib2, 11, Nle14)hGIP(1-42)-OH (서열번호 48);
(Aib2, A5c11)hGIP(1-30)-NH2 (서열번호 49);
(Aib2, A5c11, A6c14)hGIP(1-30)-NH2 (서열번호 51);
(Aib2, A5c11, Nle14)hGIP(1-30)-NH2 (서열번호 53);
(Aib2, A5c11)hGIP(1-42)-OH (서열번호 56);
(Aib2, A5c11, Nle14)hGIP(1-42)-OH (서열번호 57);
(Aib2, A5c11, A6c14)hGIP(1-42)-OH (서열번호 64);
(D-Ala2, A5c11, 40)hGIP(1-42)-OH;
(D-Ala2, A5c11, His43)hGIP(1-43)-OH;
(D-Ala2, A5c11, 41)hGIP(1-42)-OH;
(Gly2, A5c11, His43)hGIP(1-43)-OH (서열번호 116);
(Gly2, A5c11, Nle14, His43)hGIP(1-43)-OH (서열번호 117); 또는
(D-Ala2, A5c11, Nle14, His43)hGIP(1-43)-OH;
또는 그의 약학적으로 허용가능한 염. - 제1항 또는 제2항에 있어서, A2가 D-Ala인 화합물 또는 그의 약학적으로 허용가능한 염.
- 제1항 또는 제2항에 있어서, A2 또는 A11가 Aib인 화합물 또는 그의 약학적으로 허용가능한 염.
- 제1항 또는 제2항에 있어서, A2가 Aib인 화합물 또는 그의 약학적으로 허용가능한 염.
- 제1항 또는 제2항에 있어서, A11은 A5c, A6c 또는 A14는 A5c, A6c 또는 Nle인 화합물 또는 그의 약학적으로 허용가능한 염.
- 제1항 또는 제2항에 있어서, A11 가 A5c, 또는 A6c인 화합물 또는 그의 약학적으로 허용가능한 염.
- 제1항 또는 제2항에 있어서, A31 내지 A43 가 결손된 화합물 또는 그의 약학적으로 허용가능한 염.
- 제1항 또는 제2항에 있어서, A2가 Ala 또는 Gly이고; A3가 Glu, 3Hyp, 4Hyp, hPro, 또는 Tic인 화합물, 또는 그의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 화합물은
[(D-Ala2, A5c11, His43])hGIP(1-43)-OH;
[(D-Ala2, A5c11, 41])hGIP(1-42)-OH;
[(Gly2, A5c11, Nle14, His43])hGIP(1-43)-OH (서열번호 117); 및
[(D-Ala2, A5c11, Nle14, His43])hGIP(1-43)-OH로 구성되는 군으로부터 선택되는 화합물 또는 그의 약학적으로 허용가능한 염. - 삭제
- 제1항에 따른 화합물을 유효량으로 포함하는, GIP-수용체 결합에 의해 매개되는 질환 또는 증상의 치료용, 또는 음식물 섭취 절제 또는 체중 감소용 약학 조성물로서, 상기 질환 또는 증상은 1형 당뇨병, 2형 당뇨병, 비만, 인슐린 내성, 포도당 불내인성, 지방간, 글루카곤증, 기도의 분비성 장애, 대사성 장애, 관절염, 골다공증, 중추신경계 질환, 재협착증, 신경퇴행성 질환, 신부전, 울혈성 심부전, 신장증 증후군, 간경변, 폐 부종, 및 고혈압으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 조성물.
- GIP-수용체 결합에 의해 매개되는 질환 또는 증상의 치료용, 또는 음식물 섭취 절제 또는 체중 감소용 약제의 제조에, 제1항 또는 제2항의 화합물 혹은 제14항의 약학적 조성물을 사용하는 방법으로서, 상기 질환 또는 증상은 1형 당뇨병, 2형 당뇨병, 비만, 인슐린 내성, 포도당 불내인성, 지방간, 글루카곤증, 기도의 분비성 장애, 대사성 장애, 관절염, 골다공증, 중추신경계 질환, 재협착증, 신경퇴행성 질환, 신부전, 울혈성 심부전, 신장증 증후군, 간경변, 폐 부종, 및 고혈압으로 이루어진 군으로부터 선택되는 것인, 방법.
- 당뇨병 관련 장애의 치료용 약제의 제조에, 제1항 또는 제2항의 화합물 혹은 제14항의 약학적 조성물을 사용하는 방법으로서, 상기 당뇨병 관련 장애는 고혈당증(hyperglycemia), 고인슐린혈증(hyperinsulinemia), 내당능 장애(impaired glucose tolerance), 공복 혈당 장애(impaired fasting glucose), 이상지질혈증(dyslipidemia), 고중성지방혈증(hypertriglyceridemia) 및 인슐린 내성(insulin resistance)으로 이루어진 군으로부터 선택되는 것인, 방법.
- 인슐린 분비 자극용 약제의 제조에, 제1항 또는 제2항의 화합물 혹은 제14항의 약학적 조성물을 사용하는 방법.
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US20062908P | 2008-12-02 | 2008-12-02 | |
US61/200,629 | 2008-12-02 | ||
PCT/US2009/004552 WO2010016940A2 (en) | 2008-08-07 | 2009-08-07 | Analogues of glucose-dependent insulinotropic polypeptide |
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KR1020117003753A KR20110043686A (ko) | 2008-08-07 | 2009-08-07 | 포도당 의존적인 인슐린 분비 자극성 폴리펩타이드의 유사체 |
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EP (2) | EP2328922A4 (ko) |
JP (2) | JP2011530508A (ko) |
KR (2) | KR101417873B1 (ko) |
CN (2) | CN104829706A (ko) |
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EP2328922A4 (en) | 2013-01-02 |
CA2732949A1 (en) | 2010-02-11 |
EP2328922A2 (en) | 2011-06-08 |
CA2732949C (en) | 2016-12-20 |
AU2009280017B2 (en) | 2013-01-10 |
US9074014B2 (en) | 2015-07-07 |
CN102171244A (zh) | 2011-08-31 |
WO2010016940A3 (en) | 2010-04-15 |
EA201170304A1 (ru) | 2011-10-31 |
JP2011530508A (ja) | 2011-12-22 |
JP2014028846A (ja) | 2014-02-13 |
KR20130093692A (ko) | 2013-08-22 |
EA020019B1 (ru) | 2014-08-29 |
CN104829706A (zh) | 2015-08-12 |
CN102171244B (zh) | 2015-05-13 |
US20110136733A1 (en) | 2011-06-09 |
WO2010016940A2 (en) | 2010-02-11 |
JP5865324B2 (ja) | 2016-02-17 |
MX2011001031A (es) | 2011-04-26 |
AU2009280017A1 (en) | 2010-02-11 |
EP2987805A2 (en) | 2016-02-24 |
KR20110043686A (ko) | 2011-04-27 |
BRPI0916890A2 (pt) | 2019-09-24 |
US20150252092A1 (en) | 2015-09-10 |
EP2987805A3 (en) | 2016-04-13 |
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