. Author manuscript; available in PMC: 2022 Apr 13.

Published in final edited form as: J Med Chem. 2020 Oct 29;63(21):12957–12977. doi: 10.1021/acs.jmedchem.0c01398

Table 3.

SAR of Pyridazine Wing: Pyridylmethyls


Compound	R	GLS IC₅₀ (nM)^a	A549 IC₅₀ (nM)^b	Microsomal Stability (mL/min/kg)^c		pH 7.4 Solubility (μM)^d
Compound	R	GLS IC₅₀ (nM)^a	A549 IC₅₀ (nM)^b	Hum	Rat	pH 7.4 Solubility (μM)^d
14		71	246	10	3	80
15		67	643	4	8	33
16		42	130	4	55	69
17		49	103	2	0.4	15
18		22	50	22	16	90
19		46	86	9	25	91
20		10	8	23	56	6

Inhibition of purified recombinant human GLS-1 (GAC isoform) assessed via a dual-coupled enzyme assay. IC₅₀ values are reported as the mean of at least three determinations. Standard deviations and counts are included in the supporting information.

Inhibition of proliferation of A549 cells. IC₅₀ values are reported as the mean of at least three determinations. Standard deviations and counts are included in the supporting information.

Liver microsomal intrinsic clearance (mL/min/kg protein).

Kinetic aqueous solubility (μM) in phosphate buffer (100 mM) at pH 7.4; shaken for 1 hour at RT.