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.

Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice

“…Because of the specific expression of CCR8 on hepatic macrophages and its significant functional involvement in the progression of injury and fibrosis, CCR8 may represent an attractive target for the treatment of chronic liver diseases. Interestingly, several small molecular agonistic and antagonistic drugs have been developed for either CCR8 or CCL1 32, 33. Thus, based on our results, CCR8 antagonism by small‐molecule inhibitors may represent a feasible, promising novel antifibrogenic approach in inflammatory liver diseases.…”

C–H Methylation of Heteroarenes Inspired by Radical SAM Methyl Transferase

“…4 For example, a molecular unit as small as methyl can improve the IC 50 value of a drug candidate 100-fold in a phenomenon called the “magic methyl effect”. 5,6 In light of these merits, “a call for new C–H methylation reactions” was made recently to encourage academic and industrial chemistry research groups to study the topic in detail. 6 …”

Fragment library screening reveals remarkable similarities between the G protein-coupled receptor histamine H4 and the ion channel serotonin 5-HT3A

“…4). 22 As a result of these strong non-hydrophobic interactions 23 between ionizable H-bonding partners, many H 4 R ligands (including the high affinity endogenous ligand histamine) can bind the receptor with a high lipophilic efficiency, 24 explaining the relatively low c  log  P values of H 4 R ligand (Fig. 3).…”