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  3. Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis

Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis

  • Eur J Med Chem. 2020 Feb 15;188:112006. doi: 10.1016/j.ejmech.2019.112006.
Massimiliano Runfola 1,  Simona Sestito 1,  Lorenza Bellusci 2,  Valeria La Pietra 3,  Vincenzo Maria D'Amore 3,  Marta Anna Kowalik 4,  Grazia Chiellini 5,  Sheraz Gul 6,  Andrea Perra 4,  Amedeo Columbano 4,  Luciana Marinelli 3,  Ettore Novellino 3,  Simona Rapposelli 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Pisa, 56126, Italy.
  • 2 Department of Pathology, University of Pisa, Pisa, 56126, Italy.
  • 3 Department of Pharmacy, University of Naples Federico II, Italy.
  • 4 Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy.
  • 5 Department of Pathology, University of Pisa, Pisa, 56126, Italy. Electronic address: grazia.chiellini@unipi.it.
  • 6 Fraunhofer Institute for Molecular Biology & Applied Ecology - ScreeningPort, Hamburg, Germany.
  • 7 Department of Pharmacy, University of Pisa, Pisa, 56126, Italy; Interdepartmental Research Centre for Biology and Pathology of Aging, University of Pisa, Pisa, Italy. Electronic address: simona.rapposelli@unipi.it.
PMID: 31931337 DOI: 10.1016/j.ejmech.2019.112006
Abstract

Although triiodothyronine (T3) induces several beneficial effects on lipid metabolism, its use is hampered by toxic side-effects, such as tachycardia, arrhythmia, heart failure, bone and muscle catabolism and mood disturbances. Since the α isoform of thyroid hormone receptors (TRs) is the main cause of T3-related harmful effects, several efforts have been made to develop selective agonists of the β isoform that could induce some beneficial effects (i.e. lowering triglyceride and Cholesterol levels reducing obesity and improving metabolic syndrome), while overcoming most of the adverse T3-dependent side effects. Herein, we describe the drug discovery process sustained by ADME-Toxicity analysis that led us to identify novel agonists with selectivity for the isoform TRβ and an acceptable off-target and absorption, distribution metabolism, excretion and toxicity (ADME-Tox) profile. Within the small series of compounds synthesized, derivatives 1 and 3, emerge from this analysis as "potentially safe" to be engaged in preclinical studies. In in vitro investigation proved that both compounds were able to reduce lipid accumulation in HepG2 and promote lipolysis with comparable effects to those elicited by T3, used as reference drug. Moreover, a preliminary in vivo study confirmed the apparent lack of toxicity, thus suggesting compounds 1 and 3 as new potential TRβ-selective thyromimetics.

Keywords

Fatty-liver disorder; Liver regeneration; TRβ selective agonist; Thyronamine; Triiodothyronine.

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