1. Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4)
- Author
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Eidam Hilary Schenck, Theresa J. Roethke, Linda S. Barton, Fox Ryan Michael, Steve Zhao, Kevin S. Thorneloe, David J. Behm, Guosen Ye, Patrick Stoy, Mui Cheung, Tram H. Hoang, Dennis A. Holt, Krista B. Goodman, Brian G. Lawhorn, Marlys Hammond, Mark A. Hilfiker, Carl Brooks, and Jaclyn R. Patterson
- Subjects
TRPV4 ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Pharmacology ,medicine.disease ,Pulmonary edema ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Transient receptor potential channel ,Pharmacokinetics ,In vivo ,Heart failure ,Drug Discovery ,medicine ,Potency ,Ion channel - Abstract
[Image: see text] GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.
- Published
- 2019
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