α-methyl-γ-butyrolactone | 1334377-53-5

• 分子结构分类: 有机化合物
• 英文名称: α-methyl-γ-butyrolactone
• 英文别名: 4-(3-Carboxybutyldisulfanyl)-2-methylbutanoic acid
• CAS: 1334377-53-5
• 化学式: C₁₀H₁₈O₄S₂
• 分子量: 266.383
• InChiKey: WQNCNLGGMQCJMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  16
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  125
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  α-methyl-γ-butyrolactone 、 帕潘立酮 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 36.33h， 生成
  参考文献：
  名称：

  Dual Modulation of Human P-Glycoprotein and ABCG2 with Prodrug Dimers of the Atypical Antipsychotic Agent Paliperidone in a Model of the Blood–Brain Barrier

  摘要：

  Many atypical antipsychotic drugs currently prescribed for the treatment of schizophrenia have limited brain penetration due to the efflux activity of ATP-binding cassette (ABC) transporters at the blood brain barrier (BBB), including Pglycoprotein (P-gp) and ABCG2. Herein, we describe the design and synthesis of the first class of homodimeric prodrug dual inhibitors of P-gp and ABCG2. These inhibitors are based on the structure of the atypical antipsychotic drug paliperidone (Pal), a transport substrate for both transporters. We synthesized and Characterized a small library of homodimeric bivalent Pal inhibitors that contain a variety of tethers joining the two monomers via ester linkages. The majority of our compounds were low micromolar to sub-micromolar inhibitors of both P-gp and ABCG2 in cells overexpressing these transporters and in immortalized human hCMEC/D3 cells that are derived from the BBB. Our most potent dual inhibitor also contained an internal disulfide bond in the tether (Pal-8SS) that allowed for rapid reversion to monomer in the presence of reducing agents or plasma esterases. To increase stability against these esterases, we further engineered Pal-855 to contain two hindering methyl groups alpha to the carbonyl of the ester moiety within the tether. The resulting diner, Pa1-8SSMe, was also a potent dual inhibitor that remained susceptible to reducing conditions but was more resistant to breakdown in human plasma. Importantly, Pal-8SSMe both accumulated and subsequently reverted to the therapeutic Pal monomer in the reducing environment of BBB cells. Thus, these molecules serve two purposes, acting as bath inhibitors of P-gp and ABCG2 at the BBB and as prodrugs, effectively delivering therapies to the brain that would otherwise be precluded.

  DOI：

  10.1021/acs.molpharmaceut.6b01044

文献信息

• Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-Glycoprotein at the Blood–Brain Barrier with Prodrug Abacavir Dimers
  作者：Hilda A. Namanja、Dana Emmert、David A. Davis、Christopher Campos、David S. Miller、Christine A. Hrycyna、Jean Chmielewski

  DOI：10.1021/ja206867t

  日期：2012.2.15

  Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood-brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and antiviral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two functions: inhibit P-gp efflux at the BBB and revert to monomeric therapeutic within cellular reducing environments. The prodrug dimers are potent P-gp inhibitors in cell culture and in a brain capillary model of the BBB. Significantly, these agents demonstrate anti-HIV activity in two T-cell-based HIV assays, a result that is linked to cellular reversion of the prodrug to abacavir. This strategy represents a platform technology that may be applied to other therapies with limited brain penetration due to P-glycoprotein.