From HTS to Market: the Discovery and Development of Maraviroc, a CCR5 Antagonist for the Treatment of HIV - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 197

Table 9.5 Potency remained high through a series of 2-alkyl-1,3,4-triazoles

O

NH

N R

hERG
binding at
300nM

Binding
IC 50

HLM T 1/2
mins Compound AV IC 90 log D

21 12 nM 13 8% 1.2 nd

N

N

N

22 9 nM 9 34% 1.1 nd

N

N

N

23 7 nM 8 30% 1.6 55

N

N

N

24 75 nM 4100 45% 2.3 22

N

N

N

Fluorination improved metabolic stability, despite a modest rise in lipophilicity
(compare 26 and 27), leading to the design of the difluorocyclohexyl fragment.
This was incorporated into 29, which exhibited good antiviral activity, meta-
bolic stability and hERG selectivity (no hERG binding at 300 nM). Fluorina-
tion has often been used as a blocking group at sites of potential
metabolism; 47,48 however, the use of 4,4-difluorocyclohexanecarboxylic acid
had been rarely described prior to disclosure of these compounds. 49 Since then,
it has become a more widely used fragment, with 74 reports in 2008 alone.