Back to Search
Start Over
Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4).
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2019 Jul 15; Vol. 10 (8), pp. 1228-1233. Date of Electronic Publication: 2019 Jul 15 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- 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.<br />Competing Interests: The authors declare the following competing financial interest(s): All authors are current or past employees of GlaxoSmithKline and/or stockholders of GlaxoSmithKline.
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 10
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 31413810
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.9b00274