DS-1971a
Inhibitor of SCN9A
Structure
In Cells
In Model Organisms
SERP ratings and comments
SERP Ratings
SERP Comments:
Good to see some PK/PD relating exposure to efficacy. It has been hypothesised efficacy in mice is driven by greater target residence, leading to free EC50=1.1nM compared to the in vitro mNa1.7 IC50=59.4nM. Whilst there is a clear difference in human dissociation half-life, this difference is less pronounced in mice. Moreover, the authors suggest their compound is 10-fold more potent than PF-05089771 which has mNa1.7 IC50=4.9nM. There is no head-to-head profiling of mouse in vivo efficacy or dissociation half-life. Pain models are very difficult to compare unless the study is done head to head. It will be important to consider the potential differences in target residence and not just in vitro IC50. It is not clear if DS-1971a is a better in vitro tool compared to PF-05089771. I couldn’t see the Nav1.9 selectivity (I assume it will be good based on the selectivity of DS-1971a for other subtypes but may be important as expressed in the same tissue).
(last updated: 28 Jul 2021 )
SERP Ratings
(last updated: 13 Aug 2021 )
SERP Ratings
SERP Comments:
This compound seems to be very well profiled. Selectivity within target family and also outside. ADME and PK/PD profiled in 4 species. Has been in phase 1 (chronic pain) and phase 2 initiated on diabetic peripheral neuropathic pain- but withdrawn, and was discontinued due to “strategic decisions” Daiichi Sankyo - Information from Cortellis database.
(last updated: 2 Sept 2021 )