BAY 1895344

BAY 1895344

BAY-1895344

BAY-1895344 (hydrochloride)

1876467-74-1

1876467-74-1(free base)

s8666, CCG-268786, CS-7574, HY-101566A

BAY-1895344 hydrochloride is a potent, orally available and selective ATR inhibitor, with IC₅₀ of 7 nM. Anti-tumor activity.

NMR https://file.selleckchem.com/downloads/nmr/S866603-BAY-1895344-hnmr-selleck.pdf

Biological Activity

In vitro, BAY 1895344 was shown to be a very potent and highly selective ATR inhibitor (IC50 = 7 nM), which potently inhibits proliferation of a broad spectrum of human tumor cell lines (median IC50 = 78 nM). In cellular mechanistic assays BAY 1895344 potently inhibited hydroxyurea-induced H2AX phosphorylation (IC50 = 36 nM). Moreover, BAY 1895344 revealed significantly improved aqueous solubility, bioavailability across species and no activity in the hERG patch-clamp assay. BAY 1895344 also demonstrated very promising efficacy in monotherapy in DNA damage deficient tumor models as well as combination treatment with DNA damage inducing therapies.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models

Journal of Medicinal Chemistry  2020, 63, 13, 7293-7325 (Article)

Publication Date (Web):June 5, 2020DOI: 10.1021/acs.jmedchem.0c00369

https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.0c00369

2-[(3R)-3-Methylmorpholin-4-yl]-4-(1-methyl-1Hpyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (BAY 1895344). Sulfonate 67 (500 mg, 0.95 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (68) (415 mg, 1.90 mmol), 2 M aq K2CO3 solution (1.4 mL), and Pd(PPh3)2Cl2 (67 mg, 0.094 mmol) were solubilized in DME (60 mL). The reaction mixture was stirred for 20 min at 130 °C under microwave irradiation. After cooling to rt, the mixture was filtered through a silicon filter and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica gel, hexane/EtOAc gradient 0–100%, followed by EtOAc/EtOH 9:1). The desired fractions were concentrated under reduced pressure and solubilized in concd H2SO4 (5 mL). The mixture was stirred for 3 h at rt. The mixture was then poured into ice and basified using solid NaHCO3. The suspension was filtered and the solid was stirred with EtOH at 40 °C, filtered, and dried under reduced pressure to give BAY 1895344 (280 mg, 0.75 mmol, 78%). LC-MS [Method 2]: Rt = 0.99 min. MS (ESI+): m/z = 376.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ = 13.44 (br s, 1H, pyrazole-NH), 8.35 (d, J = 5.32 Hz, 1H, naphthyridine), 7.56–7.68 (m, 3H, pyrazole, naphthyridine), 7.42 (br s, 1H, pyrazole), 7.27 (d, J = 5.58 Hz, 1H, naphthyridine), 6.59 (d, J = 2.03 Hz, 1H, pyrazole), 4.60–4.69 (m, 1H, morpholine), 4.23 (br d, J = 11.66 Hz, 1H, morpholine), 4.00–4.09 (m, 1H, morpholine), 3.78–3.85 (m, 1H, morpholine), 3.75 (m, 4H, methyl, morpholine), 3.69–3.74 (m, 1H, morpholine), 3.57 (m, 1H, morpholine), 1.30 (d, J = 6.59 Hz, 3H, methyl). 13C NMR (125 MHz, DMSO-d6): δ = 156.5, 145.2, 140.0, 139.6, 139.5, 138.2, 137.4, 137.4, 125.7, 117.1, 115.5, 108.2, 107.7, 70.3, 66.1, 47.3, 39.7, 37.2, 13.3. ESI-HRMS: m/z [M+H]+ calcd for C20H22N7O: 376.1886, found: 376.1879. [α]D –80.8 ± 1.04 (1.0000 g/ 100 mL CHCl3).

References

Identification of potent, highly selective and orally available ATR inhibitor BAY 1895344 with favorable PK properties and promising efficacy in monotherapy and combination in preclinical tumor models
Ulrich T, et al. AACR. 2017 July;77(13 Suppl):Abstract nr 983.

ATR inhibitor BAY 1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with the targeted alpha therapy Radium-223 dichloride in preclinical tumor models
Antje Margret Wengner, et al. AACR 2017 July;77(13 Suppl):Abstract nr 836.

////////////s8666, CCG-268786, CS-7574, HY-101566A, BAY-1895344, BAY 1895344

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