The total synthesis of jiadifenin has been accomplished. The synthesis allows us to build an SAR profile which suggests that the jiadifenin skeleton may be less desirable from the standpoint of nominating a potential drug than that of its prerearrangement precursor. The key steps of the jiadifenin problem involve the construction of two 1,3-related quaternary carbons. The paper describes how the stereochemistry was managed in this context. The issue was studied in considerable detail at the level of a then new allyl transfer reaction arising from a palladium-mediated transfer process of an allyl carbonate. By use of externally deuterated diallyl carbonate, we could probe, for the first time, the stereochemical relationship between the inter- and intramolecular versions of this process. The existence of concurrent inter- and intramolecular allylation reactions was demonstrated by deuteration experiments. While in the particular case at hand, we find very little difference in stereochemical outcome as one partitions between the inter- and intramolecular pathways, the techniques employed are applicable to other systems.

Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed. In addition, replacement of the terminal cyclopentylamide metabolic soft spot by five-membered heterocycles was investigated. From our efforts, we identified an optimal 6,7,8-substituted imidazo[1,2-a]pyridine core system and a 5-tert-butyl-1,2,4-oxadiazole as cyclopentylamide replacement leading to compounds 10 ((S)-N-(8-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide) and 33 ((S)-N-(8-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide). Both derivatives showed good pharmacological potencies in biochemical and cell-based assays combined with excellent physicochemical properties, including low to medium plasma protein binding across species. Finally, 10 and 33 were shown to be active in a rodent pharmacokinetic/pharmacodynamic (PK/PD) model after oral gavage at 15 mg kg , lowering IL-17 cytokine production in ex vivo antigen recall assays.

We report the first total synthesis of jiadifenin (1), the establishment of a modality for its biological evaluation, and the discovery of apparently more potent neurotrophic activity in fully synthetic compound 17, an intermediate en route to 1.