Table 1.

Potency, lipophilic binding efficiency, metabolic stability, and CYP inhibition data of the initial screening hit.

Compd	Stereo.	HNE IC50 [nm][a]	Clog D[b]	LipE[c]	CYP 2C9/3A4 IC50 [μm][d]
4	rac	900	–	–	–/–
5	R	200	4.2	2.5	2/10
6	S	7000	4.2	1.0	8/0.4

^[37] 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] Clog D (pH 7.5) was calculated by using a highly predictive method developed at Bayer, based on data points of experimentally determined log D values of internal pharmaceutical compounds and the Simulations Plus pK_a predictor.[23]

^[c] Calculated as LipE=pIC₅₀−log D.[24]

^[d] The capacity 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 CYP 2C9/CYP 3A4 substrate.