title: Increasing selectivity of CC chemokine receptor 8 antagonists by engineering nondesolvation related interactions with the intended and off-target binding sites.
abstract: The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERG ion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656.
authors: Department of Medicinal Chemistry, AstraZeneca R&D Lund, S-22187 Lund, Sweden. igor.shamovsky@astrazeneca.com
authors: Igor
authors: I
authors: Shamovsky
authors: Chris
authors: C
authors: de Graaf
authors: Lisa
authors: L
authors: Alderin
authors: Malena
authors: M
authors: Bengtsson
authors: Håkan
authors: H
authors: Bladh
authors: Lena
authors: L
authors: Börjesson
authors: Stephen
authors: S
authors: Connolly
authors: Hazel J
authors: HJ
authors: Dyke
authors: Marco
authors: M
authors: van den Heuvel
authors: Henrik
authors: H
authors: Johansson
authors: Bo-Göran
authors: BG
authors: Josefsson
authors: Anna
authors: A
authors: Kristoffersson
authors: Tero
authors: T
authors: Linnanen
authors: Annea
authors: A
authors: Lisius
authors: Roope
authors: R
authors: Männikkö
authors: Bo
authors: B
authors: Nordén
authors: Steve
authors: S
authors: Price
authors: Lena
authors: L
authors: Ripa
authors: Didier
authors: D
authors: Rognan
authors: Alexander
authors: A
authors: Rosendahl
authors: Marco
authors: M
authors: Skrinjar
authors: Klaus
authors: K
authors: Urbahns
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D004355:Drug Stability; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008968:Molecular Conformation; D015999:Multivariate Analysis; D016297:Mutagenesis, Site-Directed; D054401:Receptors, CCR8 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000473:Alkanes; D051638:Ether-A-Go-Go Potassium Channels; D054401:Receptors, CCR8; C022884:undecane