Qsar Studies on Human 5α-reductase Inhibitors: Unsaturated 3-carboxysteroids

Benign prostatic hyperplasia (BPH), a leading disorder of the elderly male population, is the nonmalignant enlargement of the prostate gland. It involves an increase in cell numbers in both the epithelial and stromal elements within the periurethal transition zone of the prostate (1). BPH prevalence increases with age affecting around 80% by the age of 80 years causing considerable voiding dysfunction affecting quality of life (2). Due to the circumjacent relationship of the prostate to the urethra, glandular enlargement could result in the compromise of urinary function requiring medical treatment (3). Clinically, BPH causes a constellation of symptoms known as lower urinary tract symptoms (LUTS), which include frequency, hesitancy, urgency, nocturia, slow urinary stream and incomplete emptying (4). Discovery indicating that growth and maintenance of prostatic tissue requires dihydrotestosterone has led to the development of potent steroidal 5α-reductase inhibitors. They have been found to inhibit the conversion of testosterone (T) to dihydrotestosterone (DHT) (5). Steroid 5α-reductase enzyme (3-oxo-steroid-4-ene dehydrogenase) is a membrane bound NADPH-dependent enzyme responsible for the conversion of testicular T into DHT (Fig. 1) (6). Thus, 5α-reductase dictates the cellular availability of DHT to prostatic epithelial cells and consequently modulates its growth. Russell and Wilsonís molecular cloning studies led to the identification of two genes that encode the two isozymes of 5α-reductase termed as 5α-reductase type I and II (7). Type I isozyme gene is located on the short arm of chromosome 5 and is expressed mainly in the human liver and sebaceous glands. Type II isozyme gene is located on the short arm of chromosome 2 and is expressed mainly in the prostate stromal and basal epithelial cells along with the dermal papilla of beard hair follicles and a deficiency in gene leads to male pseudohermaphroditism (8, 9). QSAR STUDIES ON HUMAN 5α-REDUCTASE INHIBITORS: UNSATURATED 3-CARBOXYSTEROIDS