Synthesis of Benzo[c]quinolizin-3-ones: Discovery and Development of Novel Inhibitors of Human Steroid 5alpha-Reducatse

Dihydrotestosterone (DHT) is produced by the NADPH-dependent reduction of testosterone (T) under catalysis of the enzyme steroid 5?-reductase (5?R) (EC 1.3.99.5). The DHT production is in many cases related to the maintenance of some pathological human diseases and endocrine disorders, so that the use of 5?R inhibitors for the possible control or suppression of DHT formation is a therapeutic target. Two different DNA-encoded isoenzymes of 5?-reductase, named type 1 and type 2 (5?R-1 and 5?R-2) are known, which transform T into DHT with different efficacy. This isozyme, involved in the transformation of testosterone to dihydrotestosterone mainly in human skin and scalp tissues, is possibly causing the development and maintenance of disorders such as acne and androgenic alopecia in men, and hirsutism in women. The reported inhibitors are benzo[c]quinolizin-3-one derivatives bearing at position 1, 4, 5, and/or 6 a methyl group and at position 8, i.e. on the aromatic ring, a full range of diverse substituents. All these compounds were tested toward 5?R-1 and 5?R-2 expressed in CHO cells resulting, in most cases, selective inhibitors of the type 1 isoenzyme, with inhibitory potencies (IC50) ranging from 7.6 to 9100 nM. A 3D QSAR model has been developed, which could be very helpful in interpreting the biological data as well as in providing new insight for the design of new inhibitors. These selective 5?R-1 inhibitors are candidates for the development of a drug for the treatment of acne and androgenic alopecia in men, hirsutism and polycystic ovarian syndrome in woman. Moreover, by the appropriate substitution at the position 8, also some potent dual inhibitors of 5?-reductase, with IC50 ranging between 93 and 166 nM for both isozymes, were found. These dual inhibitors could be developed as drugs in the treatment of 5?-reductase related diseases where total suppression of the circulating DHT is necessary, as for example in the treatment of BPH.