The synthesis of the 2-substituted thiophene 5 confirmed this hypothesis by displaying a slight increase in potency against Cat K (>10-fold increase in potency vs 2) and a good selectivity profile against Cathepsins B, L, and S.
If there is a slight want of potency here, it is not Bowie's fault, but that of Giorgio Moroder, who is responsible for the music; like so many pulsing compositions of the eighties, it is littered with hooks but twistless, lacking that leap with which Bowie, left to his own devices and desires, would take care to supply.
The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 μM and 0.33 μM respectively, a slight loss in potency compared to lead inhibitor 3.
Introduction of a 4-fluoro - substituent (7o) led to a slight decrease in potency.
Substitution of a trifluoromethyl group, 24, led to a slight loss in potency compared to 20.
In addition, a slight improvement in potency was observed for the 3-F (9) and 3-Cl (8) derivatives (IC50: 0.4 μ m).
Surprisingly, when the N- 4-aminophenyl -4-methylbenzenesulfonamido group was replaced by 3-(pyridiN- 4-aminophenyl -4-methylbenzenesulfonamidomeN- 4-aminophenyl -4-methylbenzenesulfonamido
We first replaced the N2 and N4 benzyl groups with phenyl groups, resulting in a slight decrease in potency (Table 1, 9).
The amine-containing analogue 18 showed a slight improvement in potency (IC50=0.93 μ m vs 3.3 μ m) suggesting that it may be possible to introduce a substituted nitrogen at the 4-position of the cyclohexane moiety.
Cyclisation to give 30 was carried out with a view to further improving passive permeability; this was achieved (PAMPA Papp 104 nm s−1) with only a slight drop in potency, but at the expense of lower metabolic stability.
The control compound anisomycin had nearly invariable IC50 values for the ATQ-R lines, except for a slight loss of potency versus the double mutant, whereas mefloquine was more variable and showed a 2-fold shift in multiple strains, suggesting that additional modifiers of drug resistance may have arisen in these strains.
