Modification of Core Triazolopyrazine

Modification of Core Triazolopyrazine

To assess modification of the triazole part of the core, two compounds based on imadazopyrazines were made (MMV669846 and MMV670250). Both showed reduced potency against PfNF54 vs. the corresponding parent compound MMV639565. The RLM stability of MMV670250 was found to be poor.

The imidazo[1,2-a]pyrazine ring system in MMV669846 is also the basis of the similar-looking Novartis compound KAI407, but KAI407 apparently possess a distinct mechanism of action.

Modifications to the pyrazine part of the core were not well tolerated. Several aromatic variations were tried.

Several replacements of the aromatic ring with aliphatic rings were assayed.

As most of the analogs arising from core modifications were >1 micromolar in potency, fewer were tested in RLM (though quite a few were tested in HLM). Of the 4 tested in RLM, the greatest stability had a Clint of 109, (HLM 9.5), several had HLM Clint 8 or less, particularly after moving or removing the N from the pyrazine ring. (<--need to locate primary data, since this disagrees with what is in the pictures here - MHT).

A selection of [1,2,4]triazolo[4,3‐a]pyridines were synthesized by Jamie Scott at The University of Sydney. Both ethers and amides were evaluated and found to be less potent than the corresponding triazolopyrazines