Cell permeability beyond the rule of 5

Drug discovery beyond the rule of 5 - Opportunities and challenges

“…Consequently, most oral and cellpermeable bRo5 drugs have a PSA above 140 Å 2 , established as an upper limit for oral absorption of Ro5-compliant drugs [8]. Recently, it has been highlighted that this apparent contradiction may be resolved by an appropriate conformational flexibility, potentially facilitated by high numbers of NRotB, that provides bRo5 drugs with chameleonic properties (Figure 2(a)) [7,9]. Thus, adoption of conformations in which PSA is minimized has been proposed to confer high cell permeability, while flexible adoption of other conformations with high PSA confers solubility in aqueous media.…”

“…Comprehensive investigations of three datasets consisting of drugs and clinical candidates, de novo designed macrocycles and cyclic peptides have revealed that cell permeability and oral bioavailability can be found in chemical space far outside the Ro5 [3,6,7]. Currently, these investigations suggest that oral druggable space may allow significant increases in molecular weight, polar surface area (PSA), and the number of rotatable bonds (NRotB) as compared to traditional oral drug space (Figure 1(c)) [8].…”

“…Hydrogen bond donors, however, should be strictly controlled as few oral compounds exceed six. Some orally available outliers still exist outside these limits, for example, macrocyclic peptides such as cyclosporin A and desmopressin, but low and/or variable bioavailability is usually encountered for such compounds [3,6,7]. Passive cell permeability may be an issue in bRo5 space, but can be improved through different approaches that all aim at reducing compound PSA.…”

“…Passive cell permeability may be an issue in bRo5 space, but can be improved through different approaches that all aim at reducing compound PSA. The most common tactics can be delineated as conformational shielding of polar groups by adjacent bulky lipophilic substituents, covalent modifications of amide bonds, induction of intramolecular hydrogen bonds (IMHB), and macrocyclization [7]. Compounds in bRo5 space usually display significant transporter-mediated efflux, but our understanding of how structural features influence efflux in bRo5 space is currently limited by lack of data [7].…”

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…154 The turn-like structure of 1,5-disubstituted 1,2,3-triazoles makes them excellent motifs for incorporation into macrocycles. 155 Two different strategies can be employed for the introduction of a 1,5-disubstituted triazole in a macrocycle.…”