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The aldo-keto reductase (AKR) enzymes constitute a family of related NADPH-dependent oxidoreductases. The ¹C subfamily (AKR1C) includes four human hydroxysteroid dehydrogenases, with AKR1C1 being a 20α-HSD and the other three being 3α-HSDs. AKR1C1 metabolizes progesterone to an inactive progestin, 20α-hydroxy progesterone. In addition, AKR1C1 actions have been implicated in cancer and in the processing of neuroactive steroids involved in brain function. 3-bromo-5-phenyl Salicylic acid selectively inhibits AKR1C1 (K_i = 4 nM) over AKR1C2 (K_i = 87 nM), AKR1C3 (K_i = 4.2 μM), and AKR1C4 (K_i = 18.2 μM). Moreover, it potently inhibits the metabolism of progesterone by bovine aortic endothelial cells overexpressing AKR1C1 (IC₅₀ = 460 nM).

AKR1C1-IN-1 is a potent and selective inhibitor of human 20α-hydroxysteroid dehydrogenase (AKR1C1), with a Ki value of 4 nM for AKR1C1[1].

[1] El-Kabbani O, et al. Structure-guided design, synthesis, and evaluation of salicylic acid-based inhibitors targeting a selectivity pocket in the active site of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1). J Med Chem. 2009 May 28;52(10):3259-64. DOI:10.1021/jm9001633