BOC-Trp-L-3-(2-naphthyl)alanyl-Asp-phenylalaninol

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: BOC-Trp-L-3-(2-naphthyl)alanyl-Asp-phenylalaninol
• 英文别名: Boc-Trp-2Nal-Asp-Phe-ol；(3S)-4-[[(2S)-1-hydroxy-3-phenylpropan-2-yl]amino]-3-[[(2S)-2-[[(2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-3-naphthalen-2-ylpropanoyl]amino]-4-oxobutanoic acid
• 化学式: C₄₂H₄₇N₅O₈
• 分子量: 749.864
• InChiKey: NYMKSUGZOSRMRN-SNZVYYTPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  55
• 可旋转键数：
  18
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  199
• 氢给体数：
  7
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  BOC-L-色氨酸羟基琥珀酰亚胺酯 在 10percent Pd/C 氢气 、 碳酸氢钠 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 乙二醇二甲醚 为溶剂， 反应 4.0h， 生成 BOC-Trp-L-3-(2-naphthyl)alanyl-Asp-phenylalaninol
  参考文献：
  名称：

  Development of Peptide 3D Structure Mimetics:  Rational Design of Novel Peptoid Cholecystokinin Receptor Antagonists

  摘要：

  The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly(29)-Trp(30)-Met(31)-Asp(32)-Phe(33)-NH2. Nevertheless, this congruence has not precluded using this structure to develop selective ligands for either CCK1 or CCK2 receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK1 tripeptide antagonists, typified by N-t-BOC-Trp-2-Nal-Asp-2-(phenyl)ethylamide (pK(B) 6.8 +/- 0.3). Molecular modeling was used to identify the bioactive conformation of these CCK1-selective compounds and prompted the design of new peptoid structures. We aimed to maintain the conformation of the parent series by exploiting patterns of hydrogen-bonding and pi-stacking interactions present in the original molecule, rather than introducing additional covalent bonds. The prototype, N-(succinyl-o-Asp-2-phenylethylamido)-L-Trp-2-( 2-naphthyl) ethylamide, was a potent and selective CCK1 antagonist (pK(B) 7.2 +/- 0.3). Furthermore, the new series showed patterns of biological activity that mirrored those of the parent tripeptides. These compounds contain elements of both peptide primary and secondary structure and represent a novel approach to designing peptidomimetics. Interesting results were obtained from comparing models of a representative tripeptide CCK1 antagonist with a conformation of CCK30-33 that others have proposed to be responsible for its activity at the CCK2 receptor. The results suggest that CCK1 and CCK2 receptors recognize enatiomeric dispositions of the Trp(30) indole, Asp(32) carboxylic acid, and C-terminal phenyl groups arrayed about a common backbone configuration. This "functional chirality" may underpin the mechanism by which these closely related receptor systems bind CCK30-33 and explain patterns of selectivity observed with optical isomers of a number of peptoid and nonpeptide ligands.

  DOI：

  10.1021/jm000937a

文献信息

• TETRAPEPTIDE DERIVATIVES AND ANALOGUES
  申请人：JAMES BLACK FOUNDATION LIMITED

  公开号：EP0563132A1

  公开（公告）日：1993-10-06
• US5486597A
  申请人：——

  公开号：US5486597A

  公开（公告）日：1996-01-23
• [EN] TETRAPEPTIDE DERIVATIVES AND ANALOGUES
  申请人：——

  公开号：WO1992011284A1

  公开（公告）日：1992-07-09

  [EN] The invention provides compounds which display antagonist or partial agonist activity at gastrin and/or cholecystokinin receptors. The compounds are of formula (I), wherein R1 is H or (a) R2, R3, R4, R5 and R6 are independently H or methyl, R7, is H, methyl, ethyl, benzyl or formyl, R8 and R10 are independently C1 to C3 alkylene or are absent, R9 is C1 to C3 alkylene or is linked to R6 to form a 3- to 6-membered cycloalkyl group or is absent, R11 is an N-blocking group and R12 is H or methyl, or R11 and R12 are linked to form an N-blocking group, B1, B2 and B3 are independently -CH2- or a carbonyl group, Y is -CO2H, tetrazole or CONR13R14 (wherein R13 and R14 are independently H or C1 to C6 hydrocarbyl), Z1 and Z2 (which may be the same or different) are optional and each represents one or more substituents in the aromatic ring system, such substituents being independently selected from C1 to C6 alkyl (two such alkyl substituents optionally forming a ring fused to one or both of the aromatic rings), C1 to C6 alkoxy, C1 to C6 thioalkoxy, carboxy, C1 to C6 carboalkoxy, nitro, trihalomethyl, hydroxy, -NR15R16 (wherein R15 and R16 are independently H or C1 to C6 alkyl), C1 to C6 alkylaryl, C1 to C6 alkyl(substituted aryl), halo, sulphonamide and cyano, and D is -O-R17-Q or (b), (wherein Q is H or a carbocyclic or heterocyclic group which may optionally be substituted; R17 is absent or is C1 to C10 hydrocarbylene, optionally substituted by -OH, -SH, halogen, -CO2R19 or -CONR19R20 (wherein R19 and R20 are independently H or C1 to C6 hydrocarbyl), and optionally having up to three carbon atoms replaced by -O-, -S- or -NR21- (wherein R21 is H or an N-blocking group), provided that R17 contains at least one carbon atom if Q is H and that R17 does not contain -O-O-; and R18 is H or C1 to C6 alkyl or forms an alkylene (eg C1 to C4 alkylene) link to Q) and pharmaceutically acceptable salts thereof.
  [FR] Composés présentant une activité antagoniste ou agoniste partielle envers des récepteurs de gastrine et/ou cholécystokinine. Les composés sont de formule (I) dans laquelle R1 est H ou (a) R2, R3, R4, R5 et R6 sont indépendamment H ou méthyl, R7 est H, méthyle, éthyle, benzyle ou formyle; R8 et R10 sont indépendamment de l'alkylène C1 à C3 ou sont absents, R9 est un alkylène C1 à C3 ou est lié à R6 de façon à former un groupe cycloalkyle comportant de 3 à 6 chaînons ou est absent, R11 est un groupe de blocage N et R12 est H ou méthyle, ou R11 et R12 sont liés de façon à former un groupe de blocage N, B1, B2 et B3 sont indépendamment -CH2- ou un groupe carbonyle, Y est -CO2H, du tétrazole ou CONR13R14 (dans laquelle R13 et R14 sont indépendamment H ou un hydrocarbyle C1 à C6), Z1 et Z2 (qui peuvent être identiques ou différents) sont facultatifs et représentent chacun un ou plusieurs substituants dans le système cyclique aromatique, de tels substituants étant sélectionnés indépendamment d'un alkyle C1 à C6 (deux de tels substituants formant éventuellement un cycle fusionné à un ou deux des cycles aromatiques), un alkoxy C1 à C6, un thioalkoxy C1 à C6, un carboxy, un carboalkoxy C1 à C6, un nitro, un trihalométhyle, un hydroxy, -NR15R16 où R15 et R16 sont indépendamment H ou un alkyle C1 à C6), un alkylaryle C1 à C6, un alkyle (aryle substitué) C1 à C6, un halo, un sulphonamide et un cyano, et D représente -O-R17-Q ou (b) (dans laquelle Q est H ou un groupe carbocyclique ou hétérocyclique qui peut être éventuellement substitué; R17 est absent ou est du hydrocarbylène C1 à C10, éventuellement substitué par -OH,-SH, de l'halogène, -CO2R19 ou CONR19R20 (dans laquelle R19 et R20 sont indépendamment H ou un hydrocarbyle C1 à C6), et ayant éventuellement jusqu'à trois atomes de carbone remplacés par -O-, -S- ou -NR21- (dans laquelle R21 est H ou un groupe de blocage N), à condition que R17 contienne au moins un atome de carbone si Q est H et que R17 ne contienne pas -O-O-; et R18 est H ou un alkyle C1 à C6 ou forme une
• Development of Peptide 3D Structure Mimetics:  Rational Design of Novel Peptoid Cholecystokinin Receptor Antagonists
  作者：Caroline M. R. Low、James W. Black、Howard B. Broughton、Ildiko M. Buck、Jonathan M. R. Davies、David J. Dunstone、Robert A. D. Hull、S. Barret Kalindjian、Iain M. McDonald、Michael J. Pether、Nigel P. Shankley、Katherine I. M. Steel

  DOI：10.1021/jm000937a

  日期：2000.9.1

  The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly(29)-Trp(30)-Met(31)-Asp(32)-Phe(33)-NH2. Nevertheless, this congruence has not precluded using this structure to develop selective ligands for either CCK1 or CCK2 receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK1 tripeptide antagonists, typified by N-t-BOC-Trp-2-Nal-Asp-2-(phenyl)ethylamide (pK(B) 6.8 +/- 0.3). Molecular modeling was used to identify the bioactive conformation of these CCK1-selective compounds and prompted the design of new peptoid structures. We aimed to maintain the conformation of the parent series by exploiting patterns of hydrogen-bonding and pi-stacking interactions present in the original molecule, rather than introducing additional covalent bonds. The prototype, N-(succinyl-o-Asp-2-phenylethylamido)-L-Trp-2-( 2-naphthyl) ethylamide, was a potent and selective CCK1 antagonist (pK(B) 7.2 +/- 0.3). Furthermore, the new series showed patterns of biological activity that mirrored those of the parent tripeptides. These compounds contain elements of both peptide primary and secondary structure and represent a novel approach to designing peptidomimetics. Interesting results were obtained from comparing models of a representative tripeptide CCK1 antagonist with a conformation of CCK30-33 that others have proposed to be responsible for its activity at the CCK2 receptor. The results suggest that CCK1 and CCK2 receptors recognize enatiomeric dispositions of the Trp(30) indole, Asp(32) carboxylic acid, and C-terminal phenyl groups arrayed about a common backbone configuration. This "functional chirality" may underpin the mechanism by which these closely related receptor systems bind CCK30-33 and explain patterns of selectivity observed with optical isomers of a number of peptoid and nonpeptide ligands.