DS-1971a

Inhibitor of SCN9A

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

SCN9A

Inhibitor

Probe Availability:

In Vitro Validations

No in Vitro Validations

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Cell:

Within Target Family: Weak inhibitory activity was observed against hNaV1.2 and hNaV1.6. DS-1971a possessed superior selectivity against hNaV1.1 and hNaV1.5. No activity against hNaV1.3, hNaV1.4, hNaV1.8. The effect of DS-1971a on the potassium currents through hERG was evaluated via the whole-cell manual patch-clamp method, demonstrating low inhibitory activity against the hERG channel.

Outside Target Family: Activity of DS-1971a against 67 receptors, channels, and transporters was evaluated by radioligand binding assays at 10 μM to confirm the absence of significant responses (≥50% inhibition).

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

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

In Cell Rating

In Model Organisms

(last updated: 13 Aug 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

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 )