. Author manuscript; available in PMC: 2021 Mar 15.

Published in final edited form as: Bioorg Med Chem. 2020 Jan 31;28(6):115349. doi: 10.1016/j.bmc.2020.115349

Table 1.

Properties of series IV inhibitors

compound	λ_max (nm) ligand-bound	ΔA_max (%)^a	K_s^b μM	IC₅₀^c μM	IC₅₀/K_s	ΔT_m^d °C	k_fast^e s⁻¹	k^ET_fast^f s⁻¹
5-atom R₁-R₂ spacer, pyridyl-methyl linker R₁-N-phenyl/R₂-indole
8f (rac,S)	422	111	0.074±0.003	0.320±0.018	4.3	+4.0	2.7 (55%)	0.061 (23%)
5a (rac,R)	422	104	0.086±0.003	0.085±0.005	1.0	+2.5	7.5 (39%)	0.047 (35%)
R₁-N-phenyl/R₂-naphthalene
5b (rac,rac)	422	107	0.070±0.002	0.055±0.005	0.8	+3.3	6.5 (40%)	0.038 (36%)
4-atom R₁-R₂ spacer pyridyl-ethyl linker R₁-phenyl/R₂-indole
7a (S, R)	422	108	0.062± 0.002	0.173±0.016	2.8	+3.8	4.1 (49%)	0.015 (46%)
7b (R, S)	422	110	0.085± 0.002	0.102±0.009	1.2	+4.1	6.8 (43%)	0.020 (28%)
pyridyl-ethyl linker R₁-phenyl/R₂-naphthalene
7c (S, R)	422	110	0.052± 0.002	0.356±0.031	6.8	+4.5	9.0 (41%)	0.016 (15%)
7d (R, S)	422	108	0.017± 0.001	0.075±0.006	4.4	+4.5	10.2 (43%)	0.027 (25%)
pyridyl-methyl linker R₁-naphthalene/R₂-naphthalene
9a (rac,rac)	421	98	0.190±0.010	0.244±0.012	1.3	+4.0	1.3 (33%)	0.035 (32%)
pyridyl-ethyl linker R₁-naphthalene/R₂-naphthalene
9b (rac,rac)	422	105	0.037± 0.002	0.218±0.0235	5.9	+4.1	3.9 (33%)	0.027 (41%)

^a–

Maximal absorbance change in the ferric ligand-bound CYP3A4 was calculated from the difference spectra (Figure S1) and expressed as a percentage relative to that induced by ritonavir.

^b-

Spectral dissociation constant for the CYP3A4-inhibitor complex determined from titration plots.

^c–

The half maximal inhibitory concentration for the BFC debenzylase activity of CYP3A4.

^d–

Ligand-dependent change in the melting temperature of CYP3A4.

^e,f–

Rate constants for the fast phase of the ligand binding reaction and reduction of the ligand-bound CYP3A4 with sodium dithionite, respectively.