A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria

Abstract

The emergence of drug resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls, while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria leading to its advancement as a preclinical development candidate.

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

“…Another example is reducing the molecular weight of the DSM265 to DSM421 by replacing the SF 5 ‐aniline moiety with a series of CF 3 ‐pyridinyls. DSM421 now is a new antimalarial compound with better solubility and absorption properties than DSM265 …”

“…Drug latentiation and pro‐drug formation is a classical approach to circumvent structure‐related problems via esterification, amidation, benzylation of carboxylic acid or hydroxy/amino functional groups as well as salt formation . Other chemical modification strategies include chemical substitutions to reduce molecular weight and conjugation to carrier molecule…”

CF3‐Pyridinyl Substitution on Antimalarial Therapeutics: Probing Differential Ligand Binding and Dynamical Inhibitory Effects of a Novel Triazolopyrimidine‐Based Inhibitor on Plasmodium falciparum Dihydroorotate Dehydrogenase

“…The inhibition of pf DHODH has arisen as a therapeutic strategy to impede a broad range of invasive diseases, including malaria where the triazolopyrimidine‐based inhibitor, DSM265, has proceeded to clinical development . Recent studies have identified a potent derivative of DSM421, by substituting the SF 5 ‐aniline group of DSM265 with a series of CF 3 ‐pyridinyls, while retaining the main triazolopyrimidine scaffold towards inhibiting Plasmodium falciparum DHODH ( pf DHODH) . Experimental studies performed on the derivative compound DSM421 revealed improved solubility, a decrease in intrinsic clearance and a surge in plasma levels after oral dosing in comparison with DSM265.…”

“…Experimental studies performed on the derivative compound DSM421 revealed improved solubility, a decrease in intrinsic clearance and a surge in plasma levels after oral dosing in comparison with DSM265. DSM421 was also shown to maintain a long‐predicted half‐life in humans . The superiority of the substituted CF 3 ‐pyridinyl to the core triazolopyrimidine scaffold resulted in the improved physical and chemical properties of DSM421 while concurrently aiding in a more simplified synthetic route as opposed to DSM265 …”

“…A resolved 3D crystal structure of pf DHODH ( Figure ) in complex with DSM265 and DSM421 served as a first attempt to provide structural perspectives on the binding of these two inhibitors . However, since X‐ray crystal structures are representative static snapshots of the complexes, they do not provide a comprehensive insight on the structural dynamics and the corresponding conformations changes of associated with the differential binding of these two triazolopyrimidine‐based inhibitors, particularly the enhanced inhibitory prowess of DSM421.…”