DS-1971a

Protein target name:

SCN9A

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

100 - 1000 nM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Ion channel

Subclass:

Sodium Voltage-Gated Channel

HUGO ID:

HGNC:10597

Entrez gene ID:

6335

UNIPROT ID:

Q15858

Target alias:

PN1; ETHA; NENA; SFNP; FEB3B; NE-NA; GEFSP7; HSAN2D; Nav1.7

Probe Details

Chemical Probes Portal ID:

CPP2203

Probe alias:

cpd 6o

PubChem CID:

71711862

SMILES string:

O=S(C1=CC(Cl)=C(O[C@@H]2[C@@H](C3=CC=NN3C)CCCC2)C=C1F)(NC4=NC=NC=C4)=O

InChi Key:

OJKONCJPCULNOW-DYVFJYSZSA-N

Orthogonal probe:

PF-05089771

Physico-chemical properties

NMR:

1H NMR (400 MHz, CDCl3) δ 1.36–1.70 (4H, m), 1.85–1.96 (2H, m), 2.03–2.11 (1H, m), 2.18–2.23 (1H, m), 3.01–3.09 (1H, m), 3.93 (3H, s), 4.09–4.17 (1H, m), 6.03 (1H, d, J = 2.0 Hz), 6.47 (1H, d, J = 11.7 Hz), 7.23–7.27 (1H, m), 7.34 (1H, d, J = 2.0 Hz), 7.94 (1H, d, J = 7.8 Hz), 8.39 (1H, d, J = 6.3 Hz), 8.81 (1H, s).

Validation in Cells and Model Organisms

In cell validation

On target activity in cells

Potency in cells:

IC50

24.5 nM Human, 26.5 nM Mouse

Potency assay (cells):

high-throughput electrophysiology system (IonWorks Quattro), whole-cell manual patch clamp method

Off target activity in cells

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).

In vivo validation

Organism:

Cyno, Dog, Rat, Mouse

Dose:

1, 3, 10, 100 mg/Kg

Route of delivery:

Oral

Plasma half life:

3.69 (C), 4.0 (D), 0.77 (R), 4.04 (M) h

Systemic clearance:

6.55 (C), 8.7 (D), 47 (R), 78.7 (M) mL/min/Kg

Fraction of probe bound to plasma protein:

96-99.2 % (C, M, D, H)

Cmax:

1570 (C), 1708 (D), 103 (R), 105 (M) nM

Tmax:

0.83 (C), 0.50 (D), 0.50 (R), 0.08 (M) h

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.0c00259

Reference (PMID):

32392056

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB 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).

Aug 4 2021 - 9:17pm

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.

Sep 7 2021 - 2:04pm

DS-1971a

Probe Availability

Probe Information

Target Details

PN1; ETHA; NENA; SFNP; FEB3B; NE-NA; GEFSP7; HSAN2D; Nav1.7

Probe Details

Physico-chemical properties

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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DS-1971a

Probe Availability

Probe Information

Target Details

PN1; ETHA; NENA; SFNP; FEB3B; NE-NA; GEFSP7; HSAN2D; Nav1.7

Probe Details

Physico-chemical properties

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?