BEA409

• 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: BEA409
• 英文别名: Inhibitor bea409；(2R,3R,4R,5R)-3,4-dihydroxy-N,N'-bis[(2S)-3-methyl-1-(methylamino)-1-oxobutan-2-yl]-2,5-bis[(4-thiophen-3-ylphenyl)methoxy]hexanediamide
• 化学式: C₄₀H₅₀N₄O₈S₂
• 分子量: 778.991
• InChiKey: AJZAPEZJWWQJHC-UWNKZCSISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  54
• 可旋转键数：
  19
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  232
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  4-bromobenzyl 2,2,2-trichloroacetimidate 在 四(三苯基膦)钯 、 三氟甲磺酸 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 乙醇 、 1,2-二氯乙烷 为溶剂， 反应 50.07h， 生成 BEA409
  参考文献：
  名称：

  Design and Fast Synthesis of C-Terminal Duplicated Potent C₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors

  摘要：

  tin analysis of the X-ray structure of a complex of HIV-1 protease with a linear C-2-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K-i values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K-i values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.

  DOI：

  10.1021/jm9910371

文献信息

• Antiviral protease inhibitors
  申请人：Medivir AB

  公开号：US20010044547A1

  公开（公告）日：2001-11-22

  Compounds of formula (I), wherein A and A are independently the same or different group of formula (II) wherein: R′ is H, CH 3 , C(CH 3 ) 2 ,—OR a , —N(R a ) 2 , —N(R a )OR a or -DP; R is H or CH 3 ; R a is H, C 1 -C 3 alkyl; D is a bond, alkylene, —C(═O)—, —S(O)— or S(O) 2 —; P is an optionally substituted, mono or bicyclic carbo- or hetereocycle; R″ is H, any of the sidechains found in the natural amino acids, carboxacetamide, or a group (CH 2 ) n DP; M is a bond or —C(═O)N(R′″)-; Q is absent, a bond, —CH(OH)— or CH 2 —; or R″ together with Q, M and R define an optionally substituted 5 or 6 membered carbo- or heterocyclic ring which is optionally fused with a further 5 or 6 membered carbo- or heterocyclic ring; with the proviso that R is —OR a , -, N(R a ) 2 , —N(R a )OR a or -DP, if M is a bond and Q is absent; X is H, OH, OCH 3 , Y is H, OH, OCH 3 , but X and Y are not both H; Z′ and Z″ are independently —(CH 2 ) m P where P is as defined above; n and m are independently 0, 1 or 2; and pharmaceutically acceptable salts and prodrugs thereof have utility as aspartyl protease inhibitors of HIV. They can be prepared in a facile two step synthesis from novel 2,5-di-O-benzyl-L-mannaro-1,4:6,3-dilactone intermediates.

  化合物的式子（I），其中A和A独立地是式子（II）的相同或不同的基团，其中：R'是H，CH3，C（CH3）2，—ORa，—N（Ra）2，—N（Ra）ORa或-DP; R是H或CH3; Ra是H，C1-C3烷基; D是键，烷基，—C(═O)—，—S（O）—或S（O）2—; P是一个可选的取代的，单环或双环的碳或杂环；R″是H，天然氨基酸中发现的任何侧链，羧乙酰胺或一个组（CH2）nDP; M是键或—C(═O)N（R'″）-; Q不存在，是键，—CH（OH）—或CH2—; 或R″与Q、M和R一起定义一个可选的取代的5或6元环或杂环，该环可以与另一个可选的取代的5或6元环或杂环融合；条件是，如果M是键且Q不存在，则R是—ORa，-，N（Ra）2，—N（Ra）ORa或-DP；X是H，OH，OCH3，Y是H，OH，OCH3，但X和Y不都是H；Z′和Z″独立地是—（CH2）mP，其中P如上定义；n和m独立地是0、1或2；以及其药学上可接受的盐和前药具有作为HIV天冬氨酸蛋白酶抑制剂的用途。它们可以从新的2,5-二-O-苄基-L-曼纳罗-1,4:6,3-二内酯中间体中方便地进行两步合成。
• ANTIVIRAL PROTEASE INHIBITORS
  申请人：MEDIVIR AB

  公开号：EP1005493B1

  公开（公告）日：2005-11-02
• US6291687B1
  申请人：——

  公开号：US6291687B1

  公开（公告）日：2001-09-18
• US6489364B2
  申请人：——

  公开号：US6489364B2

  公开（公告）日：2002-12-03
• Design and Fast Synthesis of C-Terminal Duplicated Potent <i>C</i>₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors
  作者：Mathias Alterman、Hans O. Andersson、Neeraj Garg、Göran Ahlsén、Seved Lövgren、Björn Classon、U. Helena Danielson、Ingmar Kvarnström、Lotta Vrang、Torsten Unge、Bertil Samuelsson、Anders Hallberg

  DOI：10.1021/jm9910371

  日期：1999.9.1

  tin analysis of the X-ray structure of a complex of HIV-1 protease with a linear C-2-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K-i values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K-i values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.