Pharmacological Characterization of a Novel 5-Hydroxybenzothiazolone-Derived β 2 -Adrenoceptor Agonist with Functional Selectivity for Anabolic Effects on Skeletal Muscle Resulting in a Wider Cardiovascular Safety Window in Preclinical Studies.

Autor:	Koziczak-Holbro M; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.) magdalena.koziczak@novartis.com., Rigel DF; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Dumotier B; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Sykes DA; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Tsao J; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Nguyen NH; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Bösch J; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Jourdain M; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Flotte L; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Adachi Y; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Kiffe M; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Azria M; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Fairhurst RA; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Charlton SJ; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Richardson BP; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Lach-Trifilieff E; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Glass DJ; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Ullrich T; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.)., Hatakeyama S; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland (M.K.-H., B.D., N.-H.N., J.B., M.J., L.F., M.K., M.A., R.A.F., B.P.R., E.L.-T., T.U., S.H.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, East Hanover, New Jersey (D.F.R.); Novartis Institutes for BioMedical Research, Novartis Pharma AG, Horsham, United Kingdom (D.A.S., S.J.C.); and Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts (J.T., Y.A., D.J.G.) shinji.hatakeyama@novartis.com.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2019 May; Vol. 369 (2), pp. 188-199. Date of Electronic Publication: 2019 Feb 28.
DOI:	10.1124/jpet.118.255307
Abstrakt:	The anabolic effects of β 2 -adrenoceptor ( β 2 -AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of β 2 -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 β 2 -AR agonist in comparison with formoterol as a representative β 2 -AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human β 2 -AR and selectivity over the β 1 -AR and β 3 -AR. 5-HOB also shows potent agonistic activity at the β 2 -AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with 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, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional β 2 -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. (Copyright © 2019 by The Author(s).)
Databáze:	MEDLINE
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