Drug-Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side-Chain Lipophilicity.
Drug-Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side-Chain Lipophilicity.
复制标题
DOI：
10.1002/anie.202004550
复制
发表时间：
2020-11-23
期刊：
影响因子：
--
通讯作者：
Lokey RS
中科院分区：
文献类型：
--
作者：
Furukawa A;Schwochert J;Pye CR;Asano D;Edmondson QD;Turmon AC;Klein VG;Ono S;Okada O;Lokey RS
Large, macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus. We generated two libraries of cyclic decapeptides with stable, cross-β conformations, and found that peptoid substitutions within the β-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing β-strands led to “chameleonic” species that were rigid in nonpolar media but highly flexible in water. Both rigid and chameleonic compounds showed high permeability over a wide lipophilicity range, with peak permeabilities differing significantly depending on scaffold rigidity. Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides, and that scaffold rigidity can be used to tune optimal lipophilicity.
登录
查看更多内容
影响因子：
64.5
作者：
Malovannaya A;Lanz RB;Jung SY;Bulynko Y;Le NT;Chan DW;Ding C;Shi Y;Yucer N;Krenciute G;Kim BJ;Li C;Chen R;Li W;Wang Y;O'Malley BW;Qin J
通讯作者：
Qin J
影响因子：
5.6
作者：
Ono S;Naylor MR;Townsend CE;Okumura C;Okada O;Lokey RS
通讯作者：
Lokey RS
DOI：
10.1016/j.ddtec.2018.03.001
发表时间：
2018-07-01
期刊：
Drug discovery today. Technologies
影响因子：
--
作者：
Caron, Giulia;Vallaro, Maura;Ermondi, Giuseppe
通讯作者：
Ermondi, Giuseppe
影响因子：
7.3
作者：
Ertl, P;Rohde, B;Selzer, P
通讯作者：
Selzer, P
影响因子：
7.3
作者：
Kawamoto, Steven A.;Coleska, Adriana;Ran, Xu;Yi, Han;Yang, Chao-Yie;Wang, Shaomeng
通讯作者：
Wang, Shaomeng