ABSTRACT
The insulin-like peptide human relaxin-2 was identified as a hormone that, among other biological functions, mediates the hemodynamic changes occurring during pregnancy. Recombinant relaxin-2 (serelaxin) has shown beneficial effects in acute heart failure, but its full therapeutic potential has been hampered by its short half-life and the need for intravenous administration limiting its use to intensive care units. In this study, we report the development of long-acting potent single-chain relaxin peptide mimetics. Modifications in the B-chain of relaxin, such as the introduction of specific mutations and the trimming of the sequence to an optimal size, resulted in potent, structurally simplified peptide agonists of the relaxin receptor Relaxin Family Peptide Receptor 1 (RXFP1) (e.g., 54). Introduction of suitable spacers and fatty acids led to the identification of single-chain lipidated peptide agonists of RXFP1, with sub-nanomolar activity, high subcutaneous bioavailability, extended half-lives, and in vivo efficacy (e.g., 64).
Subject(s)
Lipopeptides/pharmacology , Receptors, G-Protein-Coupled/agonists , Receptors, Peptide/agonists , Relaxin/analogs & derivatives , Relaxin/pharmacology , Amino Acid Sequence , Animals , Cardiovascular Diseases , Cell Line, Tumor , HEK293 Cells , Half-Life , Humans , Lipopeptides/genetics , Lipopeptides/pharmacokinetics , Male , Molecular Dynamics Simulation , Molecular Structure , Mutation , Protein Subunits , Rats, Sprague-Dawley , Relaxin/genetics , Structure-Activity RelationshipABSTRACT
A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.
Subject(s)
Pyridines/chemical synthesis , Quinolones/chemistry , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , High-Throughput Screening Assays , Humans , Microsomes, Liver/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity RelationshipABSTRACT
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.