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Design and development of novel non‐peptide agonists at natriuretic peptide receptor‐C
Author(s) -
Hobbs Adrian J,
Gane Paul,
Lumsden Natalie,
Nobles Muriel,
Rebstock AnneSophie,
Simone Michela,
Villar Inmaculada,
Worthington Roberta,
Xiao Fang,
Ahluwalia Amrita,
Selwood David
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.756.8
Subject(s) - pharmacophore , peptide , vasoprotective , natriuretic peptide , receptor , chemistry , antagonist , pharmacology , agonist , vascular smooth muscle , medicine , biochemistry , smooth muscle , nitric oxide , heart failure , organic chemistry
Endothelium‐derived C‐type natriuretic peptide (CNP) possesses several cytoprotective functions that might be key in preventing cardiovascular disease (Ahluwalia & Hobbs [2005] Trends. Pharmacol. Sci ., 26 , 162). Since many of the vasoprotective effects of CNP are mediated via natriuretic peptide receptor (NPR)‐C, this receptor might represent a novel therapeutic target. Thus, we have undertaken a multi‐disciplinary drug development programme, incorporating computer modelling, chemical synthesis and cell‐based biological screens to generate novel small molecule mimetics of CNP (i.e. NPR‐C agonists). Using the NPR‐C crystal structure (He et al. [2001] Science , 293 , 1657) as a starting point, we have (a) tested fragments of CNP to elucidate which amino acids make fundamental contact with NPR‐C; (b) modified the NPR‐C antagonist AP‐811, retaining the non‐peptide region and using pharmacophore searches to replace the peptide component; (c) manipulated the secondary conformation of CNP to replace key functional groups with spatially‐similar molecular structures. These strategies have led to the identification of a series of novel, selective, non‐peptide NPR‐C agonists that have sub‐micromolar potency to reverse vasoconstrictor‐induced Ca 2+ flux in rat isolated vascular smooth muscle cells and relax rat isolated mesenteric arteries in vitro. Such molecules represent an excellent starting point from which to develop NPR‐C agonists for the potential treatment of cardiovascular disease. Supported by The Wellcome Trust