Koziczak-Holbro, Magdalena, Rigel, Dean, Dumotier, Berengere, Sykes, David A., Tsao, Jeffrey, Nguyen, Ngoc-Hong, Bösch, Julian, Jourdain, Marie, Flotte, Ludivine, Adachi, Yuichiro, Kiffe, Michael, Azria, Moise, Fairhurst, Robin, Charlton, Steven J., Trifilieff, Estelle, Glass, David, Richardson, Brian P., Ullrich, Thomas and Hatakeyama, Shinji (2019) Pharmacological characterization of a novel 5-hydroxybenzothiazolone (5-HOB) derived β2 adrenoceptor agonist with functional selectivity for anabolic effects on skeletal muscle resulting in a wider cardiovascular safety window in preclinical studies. Journal of Pharmacology and Experimental Therapeutics. ISSN 0022-35651521-0103

Abstract

The anabolic effects of β2-adrenoceptor (β2-AR) agonists on skeletal muscle have been demonstrated in various species, including man. However, the clinical use of β2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived β2-AR agonist, (R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one, in comparison to formoterol as a representative β2-AR agonist which has been well characterized both clinically and preclinically. In vitro, 5-HOB has nanomolar affinity for the human β2-AR and functional selectivity over the β1-AR and β3-AR. 5-HOB also shows potent agonistic activity at the β2-AR in primary skeletal muscle myotubes isolated from rats, dogs, monkeys and humans, and induces hypertrophy of skeletal muscle myotubes. When compared to formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue derived membranes, in contrast a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy in rabbit sinoatrial nodes, inotropy in guinea pig left atria, and vascular relaxation in rat aortic rings when compared to formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats at doses which do not affect heart weight and ejection fraction, unlike formoterol which has similar effects in both tissues. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB when compared to formoterol. In conclusion, the pharmacological profile of 5-HOB indicates that this compound has superior tissue selectivity compared to the conventional β2-AR agonist formoterol in preclinical studies, and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle wasting conditions without cardiovascular limiting effects.

Item Type:	Article
Date Deposited:	16 Mar 2019 00:45
Last Modified:	16 Mar 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38231