Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent <i>In Vitro</i> Antileishmanial Activity: Initial SAR and Assessment of <i>In Vivo</i> Activity
Michael G. Thomas, Manu De Rycker, Richard J. Wall, Daniel Spinks, Ola Epemolu, Sujatha Manthri, Suzanne Norval, Maria Osuna‐Cabello, Stephen Patterson, Jennifer Riley, Frederick R. C. Simeons, Laste Stojanovski, John Thomas, Stephen Thompson, C.E. Naylor, José M. Fiandor, Paul G. Wyatt, María Marco, Susan Wyllie, Kevin D. Read, Timothy J. Miles, Ian H. Gilbert
Abstract
. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.
Topics & Concepts
In vivoPharmacologyTolerabilityChemistryGlucuronidationIn vitroDosingPharmacokineticsMode of actionDrug developmentVisceral leishmaniasisMechanism of actionDrugLeishmaniasisBiochemistryMedicineAdverse effectImmunologyBiologyMicrosomeBiotechnologyResearch on Leishmaniasis StudiesTrypanosoma species research and implicationsSynthesis and Biological Evaluation