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10.1111/bph.13656

http://scihub22266oqcxt.onion/10.1111/bph.13656
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C5406302!5406302!27771940
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suck abstract from ncbi


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pmid27771940      Br+J+Pharmacol 2017 ; 174 (10): 977-89
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  • Synthetic non?peptide low molecular weight agonists of the relaxin receptor 1 #MMPMID27771940
  • Agoulnik AI; Agoulnik IU; Hu X; Marugan J
  • Br J Pharmacol 2017[May]; 174 (10): 977-89 PMID27771940show ga
  • Relaxin is a small heterodimeric peptide hormone of the insulin/relaxin superfamily produced mainly in female and male reproductive organs. It has potent antifibrotic, vasodilatory and angiogenic effects and regulates the normal function of various physiological systems. Preclinical studies and recent clinical trials have shown the promise of recombinant relaxin as a therapeutic agent in the treatment of cardiovascular and fibrotic diseases. However, there are the universal drawbacks of peptide?based pharmacology that apply to relaxin: a short half?life in vivo requires its continuous delivery, and there are high costs of production, storage and treatment, as well as the possibility of immune responses. All these issues can be resolved by the development of low non?peptide MW agonists of the relaxin receptors which are stable, bioavailable, easily synthesized and specific. In this review, we describe the discovery and characterization of the first series of such compounds. The lead compound, ML290, binds to an allosteric site of the relaxin GPCR, RXFP1. ML290 shows high activity and efficacy, measured by cAMP response, in cells expressing endogenous or transfected RXFP1. Relaxin?like effects of ML290 were shown in various functional cellular assays in vitro. ML290 has excellent absorption, distribution, metabolism and excretion properties and in vivo stability. The identified series of low MW agonists does not activate rodent RXFP1 receptors and thus, the production of a RXFP1 humanized mouse model is needed for preclinical studies. The future analysis and clinical perspectives of relaxin receptor agonists are discussed. Linked Articles: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc
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