Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5

被引：152

作者：

Sebastiano, Matteo Rossi ^{[1
]}

Doak, Bradley C. ^{[2
]}

Backlund, Maria ^{[3
]}

Poongavanam, Vasanthanathan ^{[1
]}

Over, Bjorn ^{[4
]}

Ermondi, Giuseppe ^{[5
]}

Caron, Giulia ^{[5
]}

Matsson, Par ^{[6
]}

Kihlberg, Jan ^{[1
]}

机构：

[1] Uppsala Univ, Dept Chem BMC, Box 576, SE-75123 Uppsala, Sweden

[2] Monash Univ, MIPS, Dept Med Chem, 381 Royal Parade, Parkville, Vic 3052, Australia

[3] Uppsala Univ, Uppsala Univ Drug Optimizat & Pharmaceut Profilin, Dept Pharm, BMC,Sci Life Lab, SE-75123 Uppsala, Sweden

[4] AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, SE-43183 Molndal, Sweden

[5] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Quarello 15, I-10135 Turin, Italy

[6] Uppsala Univ, BMC, Dept Pharm, Box 580, SE-75123 Uppsala, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 09期

关键词：

PASSIVE MEMBRANE-PERMEABILITY; CELL-PERMEABILITY; CACO-2; MONOLAYERS; CYCLIC-PEPTIDES; PHYSICOCHEMICAL PROPERTIES; INTESTINAL-ABSORPTION; ORAL BIOAVAILABILITY; MOLECULAR-PROPERTIES; CLINICAL CANDIDATES; PROTEASE INHIBITORS;

D O I：

10.1021/acs.jmedchem.8b00347

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally diverse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds' minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous solubility depended less on the specific 3D conformation. Inspection of the crystal structures highlighted flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds as particularly effective in providing "chameleonic" properties that allow compounds to display both high cell permeability and aqueous solubility. These structural features, in combination with permeability predictions based on the correlation to solvent-accessible 3D PSA, should inspire drug design in the challenging chemical space far beyond the Ro5.

引用

页码：4189 / 4202

页数：14

共 62 条

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