A novel nonsecosteroidal VDR agonist (CH5036249) exhibits efficacy in a spontaneous benign prostatic hyperplasia beagle model

• Published in: Journal of steroid biochemistry and molecular biology Vol. 121; no. 1; pp. 204 - 207
• Main Authors: Taniguchi, K., Katagiri, K., Kashiwagi, H., Harada, S., Sugimoto, Y., Shimizu, Y., Arakawa, H., Ito, T., Yamazaki, M., Watanabe, T., Kato, A., Hoshino, E., Takahashi, T., Esaki, T., Suzuki, M., Takeda, S., Ichikawa, F., Harada, A., Sekiguchi, N., Ishigai, M., Kawata, H., Yoneya, T., Onuma, E., Sudoh, M., Aoki, Y.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Kidlington Elsevier Ltd 01.07.2010; Elsevier
• Subjects: Animals; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Biological and medical sciences; Calcium - blood; Cell Proliferation; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Micronucleus Tests; Models, Biological; Nephrology. Urinary tract diseases; Nonsecosteroidal vitamin D receptor agonist; Prostate - drug effects; Prostate - metabolism; Prostate stromal cells; Prostatic Hyperplasia - pathology; Pyridines - chemistry; Pyridines - pharmacology; Rats; Receptors, Calcitriol - agonists; Receptors, Calcitriol - metabolism; Spontaneous benign prostatic hyperplasia; Stromal Cells - cytology; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Vertebrates: endocrinology; Vertebrates: reproduction; Nonsecosteroidal vitamin D receptor agonist; Prostate stromal cells; Spontaneous benign prostatic hyperplasia; Agonist; Urinary system disease; Prostate disease; Vitamin D receptor; Benign prostatic hyperplasia; Models; Benign neoplasm; Stromal cell; Urogenital system; Male genital diseases; Prostate
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2010.03.043

To date, there have been no reports showing the efficacy of nonsecosteroidal vitamin D receptor (VDR) agonists in a benign prostatic hyperplasia (BPH) animal model. To examine the efficacy of CH5036249, a novel nonsecosteroidal VDR agonist, we orally administered the compound at 0.03 μg/kg to a beagle model with spontaneous BPH. Prostate volume was checked by rectal ultrasonic probe periodically during 11 months of administration and the prostate tissues histologically examined. CH5036249 inhibited prostate growth in two out of three dogs compared with vehicle-treated dogs. In the prostate specimens, substantial atrophy of the epithelium was observed in all dogs administered CH5036249. At the dose given, serum calcium levels slightly increased in the CH5036249-treated dogs but stayed within a normal range. We next examined the cell growth inhibition of CH5036249 using human prostate stromal cells and found the cell growth inhibitory activity of CH5036249 to be comparable to that of 1α,25(OH) 2D 3. The bioavailability from oral administration in rats was 95.1% with a t 1/2 of 17.6 h. Both micro-AMES and micronucleus tests were negative. Although the results are still preliminary, we consider the novel nonsecosteroidal VDR agonist CH5036249 to be a possible new drug candidate for the treatment of BPH in humans.