Increasing selectivity of CC chemokine receptor 8 antagonists by engineering nondesolvation related interactions with the intended and off-target binding sites.
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.
Shamovsky
Igor
I
Department of Medicinal Chemistry, AstraZeneca R&D Lund, S-22187 Lund, Sweden. igor.shamovsky@astrazeneca.com
de Graaf
Chris
C
Alderin
Lisa
L
Bengtsson
Malena
M
Bladh
Håkan
H
Börjesson
Lena
L
Connolly
Stephen
S
Dyke
Hazel J
HJ
van den Heuvel
Marco
M
Johansson
Henrik
H
Josefsson
Bo-Göran
BG
Kristoffersson
Anna
A
Linnanen
Tero
T
Lisius
Annea
A
Männikkö
Roope
R
Nordén
Bo
B
Price
Steve
S
Ripa
Lena
L
Rognan
Didier
D
Rosendahl
Alexander
A
Skrinjar
Marco
M
Urbahns
Klaus
K
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
D000473:Alkanes; D051638:Ether-A-Go-Go Potassium Channels; D054401:Receptors, CCR8; C022884:undecane