BMS 195614 is a selective RARα antagonist [1]. It can bind to the RARα subunit [5].
BMS195614,4[[[[5,6-Dihydro-5,5-dimethyl-8-(3-quinolinyl)]-2-naphthalenyl] carbonyl]amino]benzoic acid [2], was considered to be retinoid antagonists as it inhibited all-transretinoic acid-induced (ATRA-induced) retinoic acid response elements-chloramphenicol acetyltransferase (RARE-CAT) reporter expression via concomitantly transfected retinoic acid receptors (RARs) [3][4].
Retinoic acids (RAs) are the most notably biologically active derivatives (collectively referred to as retinoids) of vitamin A (retinol). Retinoic acids exert a wide variety of profound effects on cellular differentiation, vertebrate development and homeostasis [6].
BMS 195614 reversed the induction effect of selective RARα agonists, AM580, AM80 and BMS 194753 on differentiation of the acute promyelocytic leukemia cell lines, NB4 and HL60 [1]. Treatment with retinoic acid (RA) (10-6 M) for 72 hrs significantly reduced T47D breast cancer cells migration. But RA in combination with BMS 195614 did not affect the cell movement [7]. In cells of a bovine stromal-vascular fraction from intramuscular fat, BMS 195614 significantly diminished the anti-adipogenic effect of ATRA [8].
BMS 195614 displayed poor in vivo activity in mice when administered orally. Treatment with BMS 195614 at oral doses for 1 month showed no inhibition to spermatogenesis [3]. Oral administration of BMS 195614 did not suppress spermatogenesis in mice [9].
References:
[1]. F. Christopher Zusi, Matthew V. Lorenzi and Valerie Vivat-Hannah. Selective retinoids and rexinoids in cancer therapy and chemoprevention. Drug Discovery Today, 2002, 7(23):1165-1174.
[2]. John E. Starrett, Jr., David R. Tortolani, Muzammil M. Mansuri, et al. Bristol-Myers Squibb Co. Retinoid-like Heterocycles. US patent 5,559,248. 1996 Sep. 24.
[3]. Sanny S. W. Chung, Rebecca A. D. Cuellar, Xiangyuan Wang, et al. Pharmacological Activity of Retinoic Acid Receptor Alpha-Selective Antagonists in Vitro and in Vivo. ACS Med. Chem. Lett., 2013, 4: 446-450.
[4]. Eun Young Park, Alice Dillard, Elizabeth A. Williams, et al. Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism. Cancer Res., 2005, 65(21):9923-9934.
[5]. Dongchun Liang, Aijun Zuo, Hui Shao, et al. Retinoic Acid Inhibits CD25þ Dendritic Cell Expansion and cd T-Cell Activation in Experimental Autoimmune Uveitis. Invest Ophthalmol Vis Sci., 2013, 54:3493-3503.
[6]. Pierre Chamban. A decade of molecular biology of retinoic acid receptors. FASEBJ., 1996, 10:940-954.
[7]. Flamini Marina Ines, Gauna Gisel Valeria, Sottile Mayra Lis, et al. Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor β. J. Cell. Mol. Med., 2014, 18(6): 1113-1123.
[8]. Nikolas Gunkel, Thorsten Meyer and John Michael Graettinger; N/A. Method of Modulating the Degree of Adipose Tissue Deposited Intramuscularly. US patent 20140094512A1. 2014 Apr. 3.
[9]. Fern E. Murdoch and Erwin Goldberg. Male contraception: Another holy grail. Bioorg. Med. Chem. Lett., 2014, 24:419-424.