Synthesis, Antimalarial Activity, and Preclinical Pharmacology of a Novel Series of 4′-Fluoro and 4′-Chloro Analogues of Amodiaquine. Identification of a Suitable “Back-Up” Compound for N-tert-Butyl Isoquine

Abstract

On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.

JPC-2997, a New Aminomethylphenol with High In Vitro and In Vivo Antimalarial Activities against Blood Stages of Plasmodium

“…Based on these favorable in vivo efficacy data, the pharmacokinetics of JPC-2997 in healthy mice showed linear kinetics in the oral-dose range of 2.5 to 40 mg/kg. It appears to be well absorbed and exhibits biphasic decline in both blood and plasma concentrations, with a relatively long elimination half-life of 49.8 h. JPC-2997's elimination half-life is longer than those of dihydroartemisinin (25 min) (23), amodiaquine (ϳ7 h) (24), atovaquone (12 h) (25), and mefloquine (17 h) (26), and comparable to that of chloroquine (47 h) (27) but shorter than that of piperaquine (15 days) (28). Unlike the quinoline antimalarials amodiaquine (29), chloroquine (30), and pyronaridine (31), which concentrate in erythrocytes, JPC-2997 does not appear to accumulate in erythrocytes, with a blood-to-plasma concentration ratio of 0.7.…”

Role of Metabolism in Toxicity of Drugs in Humans

“…on the antimalarial agent amodiaquine [79][80][81][82][83]. The clinical use of amodiaquine is somewhat restricted by several cases of hepatotoxicity and agranulocytosis; the detection of IgG antibodies in patients exposed to the drug is consistent with an immune-mediated hypersensitivity reaction [84,85].…”

“…Exchanging the C -4-phenolic OH group with a fluorine results in 12 that does not undergo the obligatory two-electron oxidation process to form a electrophilic quinone-imine species (Scheme 11.10) [81]. An alternate approach to prevent reactive metabolite formation involved the isomerization of the 3 and 4 substituents in amodiaquine; from this exercise emerged analogs 13 and 14, which were devoid of reactive metabolite formation (judged from the lack of formation of thiol conjugates) and possessed pharmacodynamic, pharmacokinetic, and safety profiles comparable to amodiaquine (Scheme 11.10) [82,83]. Finally, against this backdrop, it is noteworthy to comment on the metabolismguided design of fluorofelbamate as a potentially safe alternative to the anticonvulsant felbamate, which is associated with many cases of life-threatening aplastic anemia and hepatotoxicity, resulting in a black box label warning and extensive monitoring requirements in the United States [86].…”

Road Towards New Antimalarials – Overview of the Strategies and their Chemical Progress

“…Currently, GSK369796 is in phase I clinical trials. Compound 11 which have similar in vitro and in vivo properties and are being studied as a backup for this series [18].…”