Application of an in house bioisosteric approach to the design of innovative inhibitors of aldo-keto reductase 1C3 (AKR1C3)

The enzyme aldo-keto reductase 1C3 (AKR1C3) plays a central role in androgen biosynthesis in prostate tissue. Since AKR1C3 was found to be overexpressed in castrate-resistant prostate cancer (CRPC), this enzyme has been investigated as an attractive therapeutic target for this disease. At the present, no selective AKR1C3-targeted agent has been approved for clinical use [1]. Some non-steroidal anti-inflammatory drugs, such as flufenamic acid, are known to inhibit AKR1C3 in micromolar range, although unselectively toward the other isoforms, C1 and C2, and COX as well. Our group recently employed a scaffold-hopping approach based on conformational restriction of benzoic acid group in flufenamic acid obtaining compound 1 (Figure 1), a potent and selective inhibitor of AKR1C3 [2]. The aim of the current work is to improve compound 1 potency and selectivity by following two strategies: modulation of the aniline portion, and bioisosteric replacement of the oxygen in the benzoisoxazole ring (Figure 1).Here we present the in silico design as well as the synthesis and the biological activity of the new designed compounds. [1] A.C. Pippione, D. Boschi, K. Pors, S. Oliaro-Bosso, and M.L. Lolli, J. Cancer Metastasis Treat. 3 (2017) 328-361. [2] A.C. Pippione, I.M. Carnovale, D. Bonanni, M. Sini, P. Goyal, E. Marini, K. Pors, S. Adinolfi, D. Zonari, C. Festuccia, W.Y. Whalgren, R. Friemann, R. Bagnati, D. Boschi, S. Oliaro-Bosso, and M.L. Lolli, Eur. J. Med. Chem. 150 (2018) 930-945.