Danicamtiv (MYK-491)

Danicamtiv (MYK-491, SAR 440181) is a novel cardiac myosin activator that enhances cardiomyocyte contraction.

Danicamtiv metabolism pathways in vitro included CYP-mediated amide-cleavage, N-demethylation, as well as isoxazole- and piperidine-ring-opening.Danicamtiv show high permeability and no efflux in a Caco-2 cell line.^{<a class="sref" href="#s_ref">[2]</a>}

Danicamtiv selectively enhances cardiac actomyosin activity, the molecular force‐generating unit of the sarcomere, prolonging contraction while preserving actin-myosin detachment, allowing relaxation, and without impacting Ca2+ homeostasis.^{<a class="sref" href="#s_ref">[1]</a>}

• Cell lines

  Caco-2/TC7 cell lines, male human hepatocytes

• Concentrations

  1 µM, 10 µM

• Incubation Time

  0, 2, 4, 6, 8, and 24 h

• Method

  Incubations of plated human hepatocytes (1.4 million viable cells/mL, 0.2 mL, n = 2) with danicamtiv (1 µM) are performed in a cell culture incubator (37 °C, 5% CO₂, 95% humidity). Incubations are quenched with 200 µL of ACN containing 50 nM CBZ internal standard at incubation times 0, 2, 4, 6, 8, and 24 h. Supernatants are analysed by LC-MS/MS for the analysis of danicamtiv from preclinical pharmacokinetic studies. Caco-2 cells are seeded on 96-well cell culture plates with PCF membrane filters and maintained for 21/25 days post-seeding with culture medium exchanged every 4th day. The bidirectional permeability (efflux) experiments are conducted on a TECAN automated liquid handling platform. Danicamtiv is examined at 1 and 10 μM, permeability controls are tested at 10 μM, and efflux controls are tested either at 2 μM or 1 μM in duplicate wells.

• Animal Models

  male beagle dogs

• Dosages

  2–3 mg/kg

• Administration

  p.o. , i. pl.