Navepdekinra

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Navepdekinra

CAS 2467732-66-5

MF C33H48FN7O4 MW625.78

1H-Pyrazole-5-carboxamide, 1-ethyl-N-[(1S)-2-[[2-fluoro-4-[(1S,2R)-1-methyl-3-(4-methyl-1-piperazinyl)-3-oxo-2-[(1-oxopropyl)amino]propyl]phenyl]amino]-1-(trans-4-methylcyclohexyl)-2-oxoethyl]-

1-ethyl-N-{(1S)-2-{2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propanamidobutan-2-yl]anilino}-1-[(1r,4S)-4-methylcyclohexyl]-2-oxoethyl}-1H-pyrazole-5-carboxamide

1-ethyl-N-{(1S)-2-{2-fluoro-4-[(2S,3R)-4-(4-methylpiperazin-1-yl)-4-oxo-3-propanamidobutan-2-
yl]anilino}-1-[(1r,4S)-4-methylcyclohexyl]-2-oxoethyl}-1H-pyrazole-5-carboxamide
interleukin-17A (IL-17A) inhibitor, anti-inflammatory, DC-806, LY4100504, DC 806, LY 4100504, Y64F9MC2QM

Navepdekinra (also known as DC-806 or LY4100504) is an experimental, orally active small-molecule inhibitor of interleukin-17A (IL-17A). It was primarily developed to treat autoimmune and inflammatory conditions, such as psoriasis, by disrupting the interaction between IL-17A and its receptor.

Key Properties and Development

Mechanism: It is a potent inhibitor with an IC50 of 10.81 nM, designed to provide an oral alternative to existing injectable IL-17 biologic therapies.
Acquisition: The drug was originally developed by DICE Therapeutics, which was acquired by Eli Lilly and Company in 2023 for approximately $2.4 billion to bolster their immunology pipeline.

Navepdekinra (DC-806) is an orally active, potent interleukin-17A (IL-17A) inhibitor (IC₅₀ = 10.81 nM). Navepdekinra disrupts the IL-17A protein-receptor interaction, suppressing the downstream pro-inflammatory signaling pathway. Navepdekinra inhibits arthritis in a collage-induced arthritis (CIA) rat model. Navepdekinra can be used for psoriasis, psoriatic arthritis, and ankylosing spondylitis

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US300737225&_cid=P12-MLRFH1-76079-1

Example 210: N-[(2R,3S)-3-{4-[(2S)-2-[(1-ethyl-1H-pyrazol-5-yl)formamido]-2-[(1r,4S)-4-methylcyclo hexyl]acetamido]-3-fluorophenyl}-1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl]propanamide) (234)

Following General Procedure R, 0.227 g, 0.310 mmol, 1.0 eq) of 82d in DMF (1 mL) were added 1-ethyl-1H-pyrazole-5-carboxylic acid (0.052 g, 0.372 mmol, 1.2 eq), DIPEA (0.43 mL, 2.482 mmol, 8.0 eq) and then HATU (0.177 g, 0.465 mmol, 1.5 eq.) and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated to dryness and the residue was purified via reverse phase column chromatography on a 120 g C18 cartridge eluting with a 5-95% H ₂O:MeCN eluent (0.1% ammonia) to afford 234 (0.025 g) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.86 (s, 1H), 8.46 (d, J=8.3 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 7.75 (t, J=8.3 Hz, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.15-7.07 (m, 1H), 7.05-6.97 (m, 2H), 4.86 (t, J=9.4 Hz, 1H), 4.53 (t, J=8.4 Hz, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.46-3.38 (m, 2H), 3.29-3.14 (m, 2H), 3.12-2.99 (m, 2H), 2.25-2.03 (m, 5H), 1.98 (s, 3H), 1.81 (ddt, J=15.0, 9.9, 5.6 Hz, 2H), 1.74-1.60 (m, 4H), 1.58-1.47 (m, 1H), 1.28 (t, J=7.1 Hz, 4H), 1.20 (d, J=7.0 Hz, 3H), 1.14-1.02 (m, 1H), 0.99 (t, J=7.6 Hz, 3H), 0.93-0.87 (m, 1H), 0.86 (d, J=6.5 Hz, 3H). UPLC-MS (basic 4 min): rt=1.76 min; m/z=626.4 for [M+H] ⁺.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021055376&_cid=P12-MLRFH1-76079-1

Example 1: Exemplary Scheme—Synthesis of Intermediate Compounds 62a-62d