Pyrazine Side Chain Modifications Ethers
The phenethyl ether side-chain on the pyrazine ring is a metabolic hot-spot and so several strategies were adopted to mitigate this risk. Some general trends are:
- Changing the length of the side-chain to anything other than 3 atoms severely lowers potency (much of the inherited data supporting this is against strain PfNF54)
- Heteroatoms within the linking side-chain lower potency with the exception of MMV669848 (not an ether - features an isoindolino-methyl group on the pyrazine ring - see later section) although this compound had poor RLM stability.
- Constraining the linear side-chain into ring systems (e.g, azetidines, pyrrolidines, pyrazoles) severely reduces potency.
SAR related to Ar-C-C-C-O side chains
SAR related to Ar-C-C-O side chains (i.e. variants on the phenethyl ether)
High potency observed with a number of variants of the Ar-C-C-O side chain. The benzylic position in the phenethyl side-chain is expected to be prone to metabolic oxidation, so several compounds having mono- and di-substitution in this position were made. Di-substitution lowered the potency considerably whereas mono-substitution with OMe, OCHF2, CH2OH, NMe2 groups retained good potency. This pattern was confirmed with the synthesis of phenyl analogues (MMV6888-96, -98 and 99) add amines. Additional substitution alpha- to the ether oxygen led to complete loss of potency (single? example MMV672626). The alpha-OCHF2 compound MMV670652, with a p-CN-phenyl group on the triazole ring, showed better RLM stability (cLogP effect). (Inherited, what is the number?)
SAR related to Ar-C-O side chains (i.e. benzylic ethers)
Chris Swain suggested the synthesis of some benzyl ethers. A single benzyl ether was present in the inherited compound set. MMV675959 was made and found to possess moderate activity (By Jo Ubels, thesis). Other benzylic ethers executed thus far are shown below. MMV693148 (OSM-S-346), MMV693149 (OSM-S-347) and MMV693150 (OSM-S-348) were evaluated at Syngene in 2016. The thioether, sulfoxide and sulfone analogs of this modification were inactive.
The undesirability of these benzylic ethers was underscored by a further exploration of structures around MMV689977, in which a further three analogs with a pyridyl benzyl ether were evaluated against their counterparts with a simple phenethyl ether, clearly indicating that benzylic ethers are problematic.
(Online activity related to these compounds: planning of ether analogs: GHI 174 and blog appeal. Planning of more analogs in July 2014: GHI 232.)
SAR related to Ar-O side chains (i.e. phenolic)
In an attempt to mitigate potential metabolic instability, A zero carbon spacer was tried. A 2-naphthol substituent on the pyrazine ring showed reasonable potency (MMV670659, IC50 114 nM) but suffered from poor RLM stability (Inherited, need the actual number). Hetero-analogs of 2-naphthol (e.g. indole, indazole, quinoline, chroman, benzisoxazole, quinazoline) exhibited reduced potency. Some substituted phenolates were metabolically more stable in vitro as well as in vivo in rat, although with reduced potency. (Inherited, need the actual numbers)
Both aromatic and aliphatic ethoxy-linked substituents were installed at the 5-position (Table X). Of the aromatic groups, the meta-substituted methyl (3) and benzyl (5) ethers were the most potent, although the phenyl (1) and 3,4-diflurophenyl (2) compounds also achieved sub-micromolar potency. The para-substituted methyl (4) and benzyl (6) ethers are both at least 5-fold less potent than their meta-substituted counterparts, and the phenyl ether (7) loses significant activity as well. Almost all of the saturated substituents at this position (8-15) are completely inactive (>10 μM), with the exception of the cyclopropyl group (8). Finally, a variety of phenyl isosteres were synthesized (16-22), several of which (16, 20) maintained sub-micromolar activity. In general, nonpolar aromatic substituents distal to the 5-position of the core seem to be favored for activity.
