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.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Brooks CA,Barton LS,Behm DJ,Eidam HS,Fox RM,Hammond M,Hoang TH,Holt DA,Hilfiker MA,Lawhorn BG,Patterson JR,Stoy P,Roethke TJ,Ye G,Zhao S,Thorneloe KS,Goodman KB,Cheung Mdoi
10.1021/acsmedchemlett.9b00274subject
Has Abstractpub_date
2019-07-15 00:00:00pages
1228-1233issue
8issn
1948-5875journal_volume
10pub_type
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