Novel Orally Active Antimalarial Thiazoles

• Published in: Journal of medicinal chemistry Vol. 54; no. 21; pp. 7713 - 7719
• Main Authors: González Cabrera, Diego, Douelle, Frederic, Feng, Tzu-Shean, Nchinda, Aloysius T, Younis, Yassir, White, Karen L, Wu, Quoc, Ryan, Eileen, Burrows, Jeremy N, Waterson, David, Witty, Michael J, Wittlin, Sergio, Charman, Susan A, Chibale, Kelly
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.11.2011; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antimalarials - chemical synthesis; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Biological Availability; Chemistry, Medicinal; Cytochrome P-450 CYP1A2 Inhibitors; Drug Interactions; Drug Resistance; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Humans; In Vitro Techniques; Injections, Intravenous; Life Sciences & Biomedicine; Malaria - drug therapy; Male; Mice; Microsomes - metabolism; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Plasmodium berghei; Plasmodium falciparum - drug effects; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - pharmacokinetics; Thiazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201108k

An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC50: 0.08 μM (K1, chloroquine and multidrug resistant strain) and 0.07 μM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 × 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t 1/2 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibited moderate potential to inhibit CYP1A2 (IC50 = 1.5 μM) and 2D6 (IC50 = 0.4 μM) as well as having a potential hERG liability (IC50 = 3.7 μM).