Table 1.

Summary of patent applications reviewed on AKR1C3 inhibitors.

Compound class	Patent number	Mode of action	Assay method	IC50 value for AKR1C3a	Specificity for AKR1C3b	Status
N-phenylsulfonyl indoles	CA 2644809 W02007100066	Enzyme inhibition	4-AD to testosterone	90 nM	Counter screen against 17BHSD3 selectivity > 100-fold	Preclinical (Astellas)
N-(benzimidazolylcarbonyl)-piperidines	JP201202018	Enzyme inhibition	4-AD to testosterone	110 nM	Counter screen against 17BHSD3	Preclinical (Astellas)
N-(indolylcarbonyl)-piperidines	WO2010101127 JP2012102017 JP2010222350	Enzyme inhibition	4-AD to testosterone	3.7 nM	AKR1C3 > AKR1C1	Lead ASP9521 (Astellas) Phase 1 clinical trial
N-(pyridinepyrroylylcarbonyl)-piperidines	W02010101128	Enzyme inhibition	4-AD to testosterone	24 nM	Not determined	Preclinical (Astellas)
N-(benzimidazoles or indole) benzoic acids	CA02694216 WO2009014150 WO2010087319	Enzyme inhibition	4-AD to testosterone	40–50 nM	Counter screen against 17BHSD3 Selectivity > 40–250-fold LNCaP-AKR1C3 cells	Preclinical
N-(phenylamino)-benzoates	WO2012122208 US 2014/0107085	COMP	Inhibits S-tetralol oxidation	60 nM	Counter screen against AKR1C1, 1C2, 1C4 Selectivity > 250-fold	Flufenamic acid isomer Preclinical
N-(naphthylamino)-benzoates	WO2012142208 US 20140107085	COMP; AR antagonist	Inhibits S-tetralol oxidation	80 nM	Counter screen against AKR1C1, 1C2, 1C4 Selectivity > 100-fold	BMT4-158 Preclinical
Isoquinolones	WO2013142390 WO2014039820	COMP; blocks AKR1C3-AR coactivator function	4-AD to testosterone	770 nM	AKR1C3 > AKR1C1	GTx-560 (GTx-Therapeutics) Preclinical
Indomethacin analogs	WO2013/059245 US 2016/0303082 WO2015065919c	COMP	Inhibits S-tetralol oxidation	90 nM	Counter screen against AKR1C1, 1C2, 1C4 Selectivity > 500-fold	Preclinical
Nitrogen or sulfur-substituted estrenes	WO2013045407 WO2014009274 WO2014128108 WO2016/037956	Enzyme inhibition	NADPH reduction of cumberone to cumberol and 4-AD to testosterone	1 nM	HEK-293-AKR1C3 cells	Preclinical (Bayer)
β-Naphthylacetic acids	W02017/070448-A120170427	COMP	Inhibits S-tetralol oxidation	110 nM	Counter screen AKR1C2 Selectivity > 400 fold	R-Ethyl-naproxen Preclinical
Baccharin	JP2015020966	COMP	Inhibits S-tetralol oxidation	100 nM	Counter screen	Preclinical
Baccharin analogs	Provisional patent				AKR1C2 Selectivity > 500-fold

COMP: Competitive inhibition; 4-AD: 4-androstene-3,17-dione; AR: androgen receptor; ND: not determined.

^aIC₅₀ value for the most potent inhibitor in the series.

^bFold selectivity for most specific compound in the series in counterscreens.

^cUse patent.