Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy

作者：Baragana Beatriz; Norcross Neil R; Wilson Caroline; Porzelle Achim; Hallyburton Irene; Grimaldi Raffaella; Osuna Cabello Maria; Norval Suzanne; Riley Jennifer; Stojanovski Laste; Simeons Frederick R C; Wyatt Paul G; Delves Michael J; Meister Stephan; Duffy Sandra; Avery Vicky M; Winzeler Elizabeth A; Sinden Robert E; Wittlin Sergio; Frearson Julie A; Gray David W; Fairlamb Alan H; Waterson David; Campbell Simon F; Willis Paul; Read Kevin D^*; Gilbert Ian H^*

来源：Journal of Medicinal Chemistry, 2016, 59(21): 9672-9685.

DOI：10.1021/acs.jmedchem.6b00723

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.

• 出版日期2016-11-10