浮米每周文献快讯：2014年10月（三）

      浮米每周文献快讯：2014年10月（三） 作者：浮米网 来源：浮米网  2014-10-27

1. 原文标题及出处：

Design, Synthesis, Structure–Function Relationship, Bioconversion, and Pharmacokinetic Evaluation of ErtapenemProdrugs

J. Med. Chem., 2014, 57 (20), pp 8421–8444

DOI: 10.1021/jm500879a

公司/组织：默克

候选药物化学结构式/活性：

                               
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靶点/作用机制：抗生素类

摘要原文：

Described here are synthesis and biological evaluations of diversified groups of over 57 ertapenemprodrugs which include alkyl, methylenedioxy, carbonate, cyclic carbonate, carbamate esters, and esters containing active transport groups (e.g., carboxyl, amino acid, fatty acids, cholesterol) and macrocyclic lactones linking the two carboxyl groups. Many of the prodrugs were rapidly hydrolyzed in rat plasma but not in human plasma and were stable in simulated gastrointestinal fluid. The diethyl ester prodrug showed the best total absorption (>30%) by intredeudenal dosing in dogs, which could potentially be improved by formulation development. However, its slow rate of the hydrolysis to ertapenem also led to the presence of large amounts of circulating monoester metabolites, which pose significant development challenges. This study also suggests that the size of susbtituents at C-2 of carbapenem (e.g., benzoic acid of ertapenem) has significant impact on the absorption and the hydrolysis of the prodrugs.

备注：

氨基甲酰类抗生素结构

                               
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2. 原文标题及出处：

Potent NonimmunosuppressiveCyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition

J. Med. Chem., 2014, 57 (20), pp 8503–8516

DOI: 10.1021/jm500862r

公司/组织：诺华

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靶点/作用机制：非免疫抑制性亲环蛋白（cyclophilin）抑制剂

摘要原文：

Nonimmunosuppressivecyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

备注：

用于治疗HCV。

3. 原文标题及出处：

Selenorhodamine Photosensitizers for Photodynamic Therapy of P-Glycoprotein-Expressing Cancer Cells

J. Med. Chem., 2014, 57 (20), pp 8622–8634

DOI: 10.1021/jm501259v

公司/组织：礼来

候选药物化学结构式/活性：

                               
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靶点/作用机制：光动力学疗法中的光敏剂

摘要原文：

We examined a series of selenorhodamines with amide and thioamide functionality at the 5-position of a 9-(2-thienyl) substituent on the selenorhodamine core for their potential as photosensitizers for photodynamic therapy (PDT) in P-glycoprotein (P-gp) expressing cells. These compounds were examined for their photophysical properties (absorption, fluorescence, and ability to generate singlet oxygen), for their uptake into Colo-26 cells in the absence or presence of verapamil, for their dark and phototoxicity toward Colo-26 cells, for their rates of transport in monolayers of multidrug-resistant, P-gp-overexpressing MDCKII-MDR1 cells, and for their colocalization with mitochondrial specific agents in Colo-26 cells. Thioamide derivatives 16b and 18b were more effective photosensitizers than amide derivatives 15b and 17b. Selenorhodaminethioamides 16b and 18b were useful in a combination therapy to treat Colo-26 cells in vitro: a synergistic therapeutic effect was observed when Colo-26 cells were exposed to PDT and treatment with the cancer drug doxorubicin

备注：

治疗表达P-糖蛋白（P-gp）的癌症。对这一类癌症而言，因存在P-gp或其他ABC转运蛋白，化疗药透过细胞膜的效率很低，故化疗药受到很大限制。

(by 浮米网)

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