Increasing Selectivity of CC Chemokine Receptor 8 Antagonists by Engineering Nondesolvation Related Interactions with the Intended and Off-Target Binding Sites

• Published in: Journal of medicinal chemistry 2009-12, Vol.52 (23), p.7706-7723
• Main Authors: Shamovsky, Igor, de Graaf, Chris, Alderin, Lisa, Bengtsson, Malena, Bladh, Håkan, Börjesson, Lena, Connolly, Stephen, Dyke, Hazel J, van den Heuvel, Marco, Johansson, Henrik, Josefsson, Bo-Göran, Kristoffersson, Anna, Linnanen, Tero, Lisius, Annea, Männikkö, Roope, Nordén, Bo, Price, Steve, Ripa, Lena, Rognan, Didier, Rosendahl, Alexander, Skrinjar, Marco, Urbahns, Klaus
• Format: Article
• Language: English
• Subjects: Alkanes - chemical synthesis; Alkanes - chemistry; Alkanes - metabolism; Alkanes - pharmacology; Binding Sites; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Line; Drug Design; Drug Stability; Ether-A-Go-Go Potassium Channels - chemistry; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - metabolism; Humans; Hydrophobic and Hydrophilic Interactions; Medical sciences; Models, Molecular; Molecular Conformation; Multivariate Analysis; Mutagenesis, Site-Directed; Pharmacology. Drug treatments; Receptors, CCR8 - antagonists & inhibitors; Receptors, CCR8 - chemistry; Receptors, CCR8 - metabolism; Structure-Activity Relationship; Substrate Specificity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900713y

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.