Improved potency of pyridin-2(1H)one derivatives for the treatment of mechanical allodynia

Improved Synthesis and Preparation of Analogues of a Pain-Relieving Pyridin-2(1H)-one

“…Compound 10 appeared to be the most effective of the three tested compounds, with a percentage of MA inhibition as high as 86%, indicating that 10 provided a better antalgic effect than the best compound previously reported (compound C: 56% inhibition). 6 In summary, an optimization of the synthesis of 3,5disubstituted pyridin-2(1H)-one A was conducted. Novel analogues of compound A were also prepared and assessed for their efficacy in preventing cutaneous mechanical allodynia in a male rat hindpaw capsaicin model, identifying compound 10 as a potent anti-allodynic agent.…”

“…Then, we found that the anti-allodynic activity could be improved by introducing a (pyridin-4-yl)amino group at the 5-position when the 3-position was substituted by an indol-4-yl moiety. 6 Unfortunately, when the second synthetic pathway was applied to the preparation of 10 , we obtained only 3% overall yield from 1 , due to the poor efficiency of steps such as Boc protection of intermediate 5 6 and subsequent halogen exchange.…”

“…Recently, we discovered a series of pyridin-2-ones with potent anti-allodynic properties (Figure 1 ). 5 6 As part of a structure–activity relationship (SAR) study, a first series of derivatives was prepared with various aryl or heteroaryl groups at the pyridinone 3-position, while the 5-position remained substituted by a phenylamino group. This led to the identification of anti-allodynic hits A and B , substituted at the 3-position by a 2-bromophenyl and an indol-4-yl group, respectively.…”

“…Compound 10 appeared to be the most effective of the three tested compounds, with a percentage of MA inhibition as high as 86%, indicating that 10 provided a better antalgic effect than the best compound previously reported (compound C : 56% inhibition). 6…”