title: Overcoming undesirable HERG potency of chemokine receptor antagonists using baseline lipophilicity relationships.
abstract: The inhibition of the hERG channel by noncardiovascular drugs is a side effect that severely impedes the development of new medications. To increase hERG selectivity of preclinical compounds, we recommend the study of nondesolvation related interactions with the intended target and hERG using a baseline lipophilicity relationship approach. While this approach is conventionally used in studies of potency, we demonstrate here that it can help in selectivity issues. Studies of hERG selectivity in four in-house classes of chemokine receptor (CCR) antagonists suggest that the selectivity is improved most effectively by structural alterations that increase the lipophilicity-adjusted primary potency, pIC 50 (CCR) - Log D. Fragment-based QSAR analysis is performed using the lipophilicity-adjusted hERG potency, pIC 50 (hERG) - Log D, to identify moieties that form nonhydrophobic interactions with the hERG channel. These moieties, which erode hERG selectivity, can then be avoided. A novel two-dimensional fragment-based QSAR analysis helps visualizing the lipophilicity-adjusted hERG and CCR potencies within chemical series.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Lund, S-22187 Lund, Sweden. igor.shamovsky@astrazeneca.com
authors.forename: Igor
authors.initials: I
authors.lastname: Shamovsky
authors.forename: Stephen
authors.initials: S
authors.lastname: Connolly
authors.forename: Laurent
authors.initials: L
authors.lastname: David
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ivanova
authors.forename: Bo
authors.initials: B
authors.lastname: Nordén
authors.forename: Brian
authors.initials: B
authors.lastname: Springthorpe
authors.forename: Klaus
authors.initials: K
authors.lastname: Urbahns
mesh_terms: D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D004364:Pharmaceutical Preparations; D026902:Potassium Channel Blockers; D019707:Receptors, Chemokine