Derivatives of pyrimidine, phthalimide and anthranilic acid as inhibitors of human hydroxysteroid dehydrogenase AKR1C1

Human hydroxysteroid dehydrogenase (HSD) AKR1C1 is a member of the aldo-keto reductase superfamily, and it functions mainly as a 20α-HSD. It catalyzes the reduction of the potent progesterone to the weak 20α-hydroxyprogesterone, and of 3α,5α-tetrahydroprogesterone (5α-THP; allopregnanolone) to 5α-pregnane-3α,20α-diol. AKR1C1 thus decreases the levels of progesterone and 5α-THP in peripheral tissue. Progesterone inhibits cell proliferation, stimulates differentiation of endometrial cells, and is also important for maintenance of pregnancy, while 5α-THP allosterically modulates the activity of the γ-aminobutyric acid receptor. Inhibitors of AKR1C1 are thus potential agents for treatment of endometrial cancer and endometriosis, as well as other diseases like premenstrual syndrome, catamenial epilepsy and depressive disorders.We have synthesized a series of pyrimidine, phthalimido and athranilic acid derivatives, and have here examined their inhibitory properties towards AKR1C1. A common aldo-keto reductase substrate, 1-acenaphthenol, was used to monitor the NAD+-dependent oxidation catalyzed by AKR1C1. The most potent inhibitors of AKR1C1 were the pyrimidine derivative N-benzyl-2-(2-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetamide (Ki = 17 μM) and the anthranilic acid derivative 2-(((2′,3-dichlorobiphenyl-4-yl)carbonyl)(methyl)amino)benzoic acid (Ki = 33 μM), both of which are non-competitive inhibitors.