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The Critical Role of Passive Permeability in Designing Successful Drugs
Author(s) -
Di Li,
Artursson Per,
Avdeef Alex,
Benet Leslie Z.,
Houston J. Brian,
Kansy Manfred,
Kerns Edward H.,
Lennernäs Hans,
Smith Dennis A.,
Sugano Kiyohiko
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000419
Subject(s) - chemistry , drug , permeability (electromagnetism) , pharmacology , solubility , drug development , in vivo , drug discovery , drug delivery , biochemical engineering , medicine , biochemistry , microbiology and biotechnology , biology , organic chemistry , engineering , membrane
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug‐drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure‐permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.