Boc-D-S-(2-naphthyl)cysteine | 159142-08-2

• 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-D-S-(2-naphthyl)cysteine
• 英文别名: (S)-2-<(tert-butoxycarbonyl)amino>-3-(2-naphthylthio)propionic acid；(S)-2-N(t-butoxycarbonyl)amino-3-naphth-2-ylthio propanoic acid；(2S)-2-N(t-butoxycarbonyl)amino-3-(naphth-2-ylthio)propanoic acid；(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-naphthalen-2-ylsulfanylpropanoic acid
• CAS: 159142-08-2
• 化学式: C₁₈H₂₁NO₄S
• 分子量: 347.435
• InChiKey: SPOKENJLTFUGBD-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Boc-D-S-(2-naphthyl)cysteine 在 盐酸 、 sodium hydroxide 、 乙酸酐 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 为溶剂， 生成 (S)-2-N(ethanoyl)amino-3-naphth-2-ylthio propanoic acid
  参考文献：
  名称：

  Inhibitors of HIV Protease useful for the treatment of Aids

  摘要：

  本发明提供了新型的HIV蛋白酶抑制剂，包括含有这些化合物的制药配方以及治疗和/或预防HIV感染和/或艾滋病的方法。

  公开号：

  US05733906A1
• 作为产物：
  描述：

  N-叔丁氧羰基-D-丝氨酸(Β-内酯) 、 sodium 2-naphthalenethiolate 以 四氢呋喃 为溶剂， 生成 Boc-D-S-(2-naphthyl)cysteine
  参考文献：
  名称：

  Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporating d-cysteine derivatives as P2/P3 moieties

  摘要：

  We designed several HIV protease inhibitors with various D-cysteine derivatives as P-2/P-3 moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV 11113 cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.05.039

文献信息

• Inhibitors of HIV protease useful for the treatment of aids
  申请人：ELI LILLY AND COMPANY

  公开号：EP0604184A1

  公开（公告）日：1994-06-29

  The present invention provides novel HIV protease inhibitors, of formula I wherein: Zis hydrogen, formyl, carbamoyl, C2-C6 alkanoyl, C1-C4 alkoxycarbonyl, -C(O)CF3 or -S(O)2-R, where Ris C1-C6 alkyl, amino, trifluoromethyl, C1-C4 alkylamino, di(C1-C4)alkylamino, aryl, aryl(C1-C4)alkyl, heterocycle, unsaturated heterocycle or C5-C7 cycloalkyl; R1is aryl, C5-C7 cycloalkyl or -S-R1x, where R1x is aryl or C5-C7 cycloalkyl; R2is an amino acid side chain, -(CH2)y-X-R2a, cyano(C1-C4)alkyl or -(CH2)y-S(O)w-[1-N(R2c)-tetrazol-5-yl], where       y is 0, 1, 2 or 3;       X is a bond, divalent(C2-C4)alkenyl, divalent(C2-C4)alkynyl, -C(O)-O-, -O-C(O)-, -C(O)-NR2b-, -NR2b-C(O)-, -NR2b-, -C(O)-, -O-, -S(O)w-;       w is 0, 1 or 2;       R2a is C1-C6 alkyl, aryl, unsaturated heterocycle, heterocycle, aryl(C1-C4)alkyl, unsaturated heterocycle(C1-C4)alkyl or heterocycle(C1-C4)alkyl;       R2b is hydrogen or C1-C4 alkyl;       R2c is hydrogen, C1-C6 alkyl, aryl, unsaturated heterocycle, aryl(C1-C4)alkyl or unsaturated heterocycle(C1-C4)alkyl; Yis aryl or unsaturated heterocycle; R3is a group having the structure: where:       p is 4 or 5;       l is 3, 4 or 5;       R4 at each occurrence is independently hydrogen, C1-C6 alkyl or hydroxy(C1-C4)alkyl;       R5 and R6 are independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, hydroxy(C1-C4)alkyl, carboxy, C1-C4 alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, aryl, heterocycle or unsaturated heterocycle; with the proviso that when Z is hydrogen, formyl, carbamoyl, C2-C6 alkanoyl or C1-C4 alkoxycarbonyl; R2 is an amino acid side chain or -(CH2)y-X-R2a, where y is 0, 1, 2 or 3; X is a bond, -C(O)-O- or -C(O)-NR2b-; R2b is hydrogen; and R2a is aryl, heterocycle or unsaturated heterocycle; then R1 must be aryl or C5-C7 cycloalkyl; or a pharmaceutically acceptable salt thereof, pharmaceutical formulations containing those compounds and methods of treating and/or preventing HIV infection and/or AIDS.

  本发明提供了式 I 的新型 HIV 蛋白酶抑制剂 其中 Z是氢、甲酰基、氨基甲酰基、C2-C6烷酰基、C1-C4烷氧基羰基、-C(O)CF3或-S(O)2-R，其中 Ris C1-C6 烷基、氨基、三氟甲基、C1-C4 烷基氨基、二（C1-C4）烷基氨基、芳基、芳基（C1-C4）烷基、杂环、不饱和杂环或 C5-C7 环烷基； R1 是芳基、C5-C7 环烷基或-S-R1x，其中 R1x 是芳基或 C5-C7 环烷基； R2 是氨基酸侧链、-(CH2)y-X-R2a、氰基(C1-C4)烷基或-(CH2)y-S(O)w-[1-N(R2c)-四唑-5-基]，其中 y 是 0、1、2 或 3； X 是键、二价(C2-C4)烯基、二价(C2-C4)炔基、-C(O)-O-、-O-C(O)-、-C(O)-NR2b-、-NR2b-C(O)-、-NR2b-、-C(O)-、-O-、-S(O)w-； w 是 0、1 或 2； R2a 是 C1-C6 烷基、芳基、不饱和杂环、杂环、芳基（C1-C4）烷基、不饱和杂环（C1-C4）烷基或杂环（C1-C4）烷基； R2b 是氢或 C1-C4 烷基； R2c 是氢、C1-C6 烷基、芳基、不饱和杂环、芳基（C1-C4）烷基或不饱和杂环（C1-C4）烷基； Y 是芳基或不饱和杂环； R3 是具有以下结构的基团 其中 p 为 4 或 5； l 是 3、4 或 5； 每次出现的 R4 独立地为氢、C1-C6 烷基或羟基（C1-C4）烷基； R5 和 R6 独立选自氢、羟基、C1-C6 烷基、C1-C6 烷氧基、氨基、C1-C4 烷基氨基、羟基（C1-C4）烷基、羧基、C1-C4 烷氧基羰基、氨基甲酰基、N-（C1-C4）烷基氨基甲酰基、芳基、杂环或不饱和杂环； 但当 Z 为氢、甲酰基、氨基甲酰基、C2-C6 烷酰基或 C1-C4 烷氧基羰基时；R2 为氨基酸侧链或-(CH2)y-X-R2a，其中 y 为 0、1、2 或 3；X 为键、-C(O)-O-或-C(O)-NR2b-；R2b 为氢； R2a 是芳基、杂环或不饱和杂环； 则 R1 必须是芳基或 C5-C7 环烷基； 或其药学上可接受的盐、 含有这些化合物的药物制剂以及治疗和/或预防 HIV 感染和/或 AIDS 的方法。
• Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains
  作者：Hirokazu Tamamura、Yasuhiro Koh、Satoshi Ueda、Yoshikazu Sasaki、Tomonori Yamasaki、Manabu Aoki、Kenji Maeda、Yoriko Watai、Hisashi Arikuni、Akira Otaka、Hiroaki Mitsuya、Nobutaka Fujii

  DOI：10.1021/jm020537i

  日期：2003.4.1

  Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only potent enzyme inhibitors (K-i = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC50 = 9.5 nM and 66 nM, respectively), even against viral strains with multidrug resistance. Furthermore, insertion of an (E)-alkene dipeptide isostere at the P-1-P-2 position of TYB5 led to development of a purely nonpeptidic protease inhibitor, TYB1 (K-i = 0.38 nM, IC50 = 160 nM).
• Potent Human Immunodeficiency Virus Type 1 Protease Inhibitors That Utilize Noncoded <scp>d</scp>-Amino Acids as P₂/P₃ Ligands
  作者：Louis N. Jungheim、Timothy A. Shepherd、Angela J. Baxter、Jeffrey Burgess、Steven D. Hatch、Penny Lubbehusen、MaryAnn Wiskerchen、Mark A. Muesing

  DOI：10.1021/jm950576c

  日期：1996.1.1

  Noncoded D-amino acids have been designed to replace the quinaldic amide-asparaginyl moiety (P-2/P-3 ligand) found in several potent human immunodeficiency virus (HIV) protease inhibitors such as LY289612. The substituted nitrogen, optimally an N-methanesulfonyl moiety, served as a CH2CONH2 (asparagine side chain mimic), while the amino acid side chain became the backbone and P-3 ligand of these novel inhibitors. Compounds derived from S-aryl-D-cysteine proved to be patent HIV protease inhibitors which also exhibited potent whole cell antiviral activity. Oxidation of the cysteines to the sulfoxide or sulfone oxidation states resulted in significant improvements in potency. For example, the compound derived from N-(methylsulfonyl)-2-S-naphthylcysteine sulfone, 17c, was a 3.5 nM inhibitor of HIV protease which inhibited the spread of virus in MT4 cells with an IC50 = 4.3 nM. Compounds 17c,g,i were found to be orally bioavailable in a rat model.
• Combination of Non-natural <scp>d</scp>-Amino Acid Derivatives and Allophenylnorstatine−Dimethylthioproline Scaffold in HIV Protease Inhibitors Have High Efficacy in Mutant HIV
  作者：Shingo Nakatani、Koushi Hidaka、Ei’ichi Ami、Koichiro Nakahara、Akihiko Sato、Jeffrey-Tri Nguyen、Yoshio Hamada、Yasuko Hori、Nobuyuki Ohnishi、Akinori Nagai、Tooru Kimura、Yoshio Hayashi、Yoshiaki Kiso

  DOI：10.1021/jm701555p

  日期：2008.5.1

  Several non-natural D-amino acid derivatives were introduced as P(2)/P(3) residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha(1)-acid glycoprotein in the test medium.
• Inhibitors of HIV protease useful for the treatment of AIDS
  申请人：ELI LILLY AND COMPANY

  公开号：EP0604185B1

  公开（公告）日：1999-03-24