TRPV4 receptors are members of the Transient Receptor Potential (TRP) superfamily of cation channels. They are highly expressed in the lung and there exists considerable evidence linking their activation to pulmonary edema, a common side-effect of heart failure (HF) which could prove fatal if left untreated. In rodent models, TRPV4 agonists 4αPDD and 5,6-EET have each demonstrated dose-dependent increases in lung permeability, and these effects can be attenuated with pre-treatment of Ruthernium Red, a nonselective TRP antagonist. Due to these experimental findings and numerous others, subtype-selective TRPV4 antagonists have the potential to serve as effective treatments for HF-induced pulmonary edema devoid of the side effects (hypertension, renal disfunction) plaguing current standards of care (diuretics, angiotensin antagonists). In this presentation, the discovery of a novel class of TRPV4 antagonists will be described, with a particular emphasis on design elements to improve lipophilic ligand efficiency (LLE), pharmacokinetic parameters (unbound clearance, oral bioavailability), and off-target activity (CYP TDI, hERG inhibition). Importantly, activity in a preclinical in vivo model predictive of therapeutic potential will be discussed, and the in vitro-in vivo correlation associated with optimized compounds will be examined.

Discovery of a novel class of TRPV4 antagonists and optimization with respect to LLE, oral PK properties and off-target activity

256th National Meeting (2018)

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