title: Non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase: synthesis, structure-activity relationships, and pharmacokinetics.
abstract: The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase by means of high-throughput screening. Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC(50) = 60 nM) with an aqueous solubility of approximately 60 μg/mL. The agent shows a 10-fold exposure (AUC/C(max)) increase in the rat model relative to 2, displays near dose proportionality in the range of 10-50 mg/kg, and exhibits good oral bioavailability (F = 39%). The significant solubility increase appears linked to the improved oral bioavailability.
authors.affiliation: Emory Institute for Drug Discovery, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
authors.forename: J Maina
authors.initials: JM
authors.lastname: Ndungu
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Krumm
authors.forename: Dan
authors.initials: D
authors.lastname: Yan
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.forename: G Prabhakar
authors.initials: GP
authors.lastname: Reddy
authors.forename: Taylor
authors.initials: T
authors.lastname: Evers
authors.forename: Randy
authors.initials: R
authors.lastname: Howard
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
authors.forename: Manohar T
authors.initials: MT
authors.lastname: Saindane
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Richard K
authors.initials: RK
authors.lastname: Plemper
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D008457:Measles / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D008459:Measles virus / Q000201:enzymology / Q000378:metabolism*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D012324:RNA-Dependent RNA Polymerase