title: Cell permeability beyond the rule of 5.
abstract: Drug discovery for difficult targets that have large and flat binding sites is often better suited to compounds beyond the "rule of 5" (bRo5). However, such compounds carry higher pharmacokinetic risks, such as low solubility and permeability, and increased efflux and metabolism. Interestingly, recent drug approvals and studies suggest that cell permeable and orally bioavailable drugs can be discovered far into bRo5 space. Tactics such as reduction or shielding of polarity by N-methylation, bulky side chains and intramolecular hydrogen bonds may be used to increase cell permeability in this space, but often results in decreased solubility. Conformationally flexible compounds can, however, combine high permeability and solubility, properties that are keys for cell permeability and intestinal absorption. Recent developments in computational conformational analysis will aid design of such compounds and hence prediction of cell permeability. Transporter mediated efflux occurs for most investigated drugs in bRo5 space, however it is commonly overcome by high local intestinal concentrations on oral administration. In contrast, there is little data to support significant impact of transporter-mediated intestinal absorption in bRo5 space. Current knowledge of compound properties that govern transporter effects of bRo5 drugs is limited and requires further fundamental and comprehensive studies.
authors.affiliation: Department of Pharmacy, BMC, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Matsson
authors.affiliation: Department of Medicinal Chemistry, MIPS, Monash University, 381 Royal Parade, Parkville, Victoria, Australia.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Doak
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Over
authors.affiliation: Department of Chemistry - BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden. Electronic address: jan.kihlberg@kemi.uu.se.
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
mesh_terms: D000284:Administration, Oral; D002463:Cell Membrane Permeability; D006801:Humans; D006860:Hydrogen Bonding; D007408:Intestinal Absorption; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations
keywords: Beyond the rule of 5; Conformational shielding; Cyclic peptides; Efflux transporters; Intramolecular hydrogen bonds; Macrocycles; Permeability; Quantitative structure permeability relationships