Table 2.

Initial shift from core bicyclic to monocyclic 2-amino-1,4-dihydropyridine systems: northern and southern SAR.

Compd	R1	R2	HNE IC50 [nm][a]	Fmax [%][b]	CYP 2C9/3A4 IC50 [μm][c]
7	NO2	Br	200	15	–/–
8	CF3	Br	200	31	0.6/0.5
9	CF3	CN	20	57	0.5/25

^[64] The inhibitory capacity of test compounds was assessed by applying functional biochemical assays with the isolated enzyme (Supporting Information); IC₅₀ values were derived from enzyme activity data (pH 7.4) in the presence/absence of various compound concentrations by applying a suitable fluorogenic peptide substrate, MeOSuc-AAPV-AMC.

^[b] The metabolic stability of test compounds was assessed in the presence of rat hepatocytes by determination of the half-life of the compound (Supporting Information). Clearance parameters and F_max values were calculated from this half-life, representing a measure of the phase 1 and phase 2 metabolism.

^[c] The potency of test compounds to inhibit human CYP 2C9 and CYP 3A4 was investigated with pooled human liver microsomes as enzyme source and selective standard substrates (Supporting Information); IC₅₀ values were derived from enzyme activity data (pH 7.4) in the presence/absence of various compound concentrations and diclofenac/midazolam as selective CYP 2C9/CYP 3A4 substrate.