Pyrazine Side Chain Modifications Amides
A library of amides (including the m-Cl benzylamide, MMV668958) gave some compounds with promising potency. However, several amides (derived from aliphatic or anilines) either showed lower potency or were inactive. The RLM of MMV668958 was poor - perhaps due to benzylic oxidation. Alpha-substitution at the benzylic position or constraining the benzylamine into an aminoindane did not improve potency. Several attempts to make aniline-amides with improved potency against Pfal failed. Loading the aniline ring with lipophilic substituents marginally improved potency but led to poor RLM stability.
The p-Cl benzanilide MMV670246, although not active against PfNF54, showed good RLM stability perhaps due to lack of benzylic metabolism. However, its rat PK showed high clearance. The potent m-Cl (MMV669542) analog had poor RLM stability.
Planning of amide analogs: GH Issues 110, 101, 123, 207, Joie Garfunkel's suggestions. Planning of more amide analogs in July 2014: GHI 232.