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

Abstract

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 microg/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 1alpha,25(OH)2D3. The bioavailability from oral administration in rats was 95.1% with a t1/2 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.

• Authors: K Taniguchi, K Katagiri, H Kashiwagi, S Harada, Y Sugimoto, Y Shimizu, H Arakawa, T Ito, M Yamazaki, T Watanabe, A Kato, E Hoshino, T Takahashi, T Esaki, M Suzuki, S Takeda, F Ichikawa, A Harada, N Sekiguchi, M Ishigai, H Kawata, T Yoneya, E Onuma, M Sudoh, Y Aoki
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 121 Issue 1-2 Pg. 204-7 (Jul 2010) ISSN: 1879-1220 [Electronic] England
• PMID: 20304062 (Publication Type: Journal Article)
• Copyright: Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Benzhydryl Compounds
• CH 5036249
• Pyridines
• Receptors, Calcitriol
• Calcium

Topics

• Animals
• Benzhydryl Compounds (chemistry, pharmacology)
• Calcium (blood)
• Cell Proliferation
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Humans
• Male
• Micronucleus Tests
• Models, Biological
• Prostate (drug effects, metabolism)
• Prostatic Hyperplasia (pathology)
• Pyridines (chemistry, pharmacology)
• Rats
• Receptors, Calcitriol (agonists, metabolism)
• Stromal Cells (cytology)