Avagacestat (BMS-708163)

Uses

Avagacestat acts as a γ-secretase inhibitor allowing for treatment of ALzheimer’s disease. On addition it has seen uses targeting embryonic signaling pathways, which control stem cell and cellular development process in cancer therapy.

Definition

ChEBI: Avagacestat is an oxadiazole and a ring assembly.

Biological Activity

bms-708163 is a potent selective and orally bioavailable inhibitor of γ-secretase with ic50 value of 0.3nm [1].the cleavage of amyloid precusor protein app by γ-secretase causes the production of aβ40 and aβ42, which are cytotoxic and cause ad. in vitro assay shows bms-708163 inhibits the formation of aβ40 and aβ42 in h4-8sw cells. it also inhibits the human recombinant cyps in vitro with ic50 value of 20μm. notch receptor is another substrate of γ-secretase. the inhibition of notch signal pathway results in some side effects. it is shown that the activity of bms-708163 to inhibit notch is 190-fold weaker than to app. in female rats, oral administration of bms-708163 significantly reduces the production of aβ in plasma and brain at 10mg/kg and 100mg/kg. in addition, bms-708163 also reduces aβ in brain and csf in male beagle dogs [1].

Synthesis

Step C. (R)-2-(4-chloro-N-(2-fluoro-4-(N'-hydroxyformamidinyl)benzyl)-benzenesulfonylamino)-5,5,5-trifluoropentanamide (246 g) was added to the reactor, followed by the addition of dry acetonitrile (509 mL), triethyl orthoformate (120 mL) and trifluoroacetic acid (7 mL). The reaction mixture was heated to 40-50 °C and the progress of the reaction was monitored by HPLC until the relative area percentage (AP) of the starting material was below 0.15. Upon completion of the reaction, a one-time addition of methanol (1.48 L) followed by water (1.034 L) was added to maintain the reaction system temperature at 45-50 °C. The reaction mixture was then cooled to 15-20 °C and the solid was collected by filtration. The filter cake was washed with a solvent mixture of acetonitrile:methanol:water (2:6:5, v/v/v) and dried under vacuum at 50-60 °C to afford (2R)-2-[N-[(4-chlorophenyl)sulfonyl]-N-[2-fluoro-4-(1 ,2,4-oxadiazol-3-yl)benzyl]amino]-5,5,5-trifluoropentanamide as a white solid (228 g, 90% yield) . 1H NMR (CDCl3, 300MHz) δ: 1.40-1.58 (m, 1H), 1.75-1.90 (m, 1H), 1.92-2.07 (m, 1H), 2.10-2.26 (m, 1H), 4.37 (dd, J = 8.67, 6.22Hz, 1H), 4.48 (d, J = 15.64Hz, 1H ), 4.64 (d, J = 15.82 Hz, 1H), 5.54 (s, 1H), 6.33 (s, 1H), 7.44-7.54 (m, 2H), 7.62 (t, J = 7.72 Hz, 1H), 7.68-7.76 (m, 3H), 7.85 (dd, J = 7.91, 1.51 Hz, 1H), 8.76 (s, 1H). 1H). 13C NMR (DMSO-d6, 75MHz) δ: 170.34, 167.75, 165.80, 159.64 (d, J = 244.5Hz, 1C), 138.19, 137.64, 131.25 (d, J = 3.75Hz, 1C), 129.31, 129.23, 129.05 (d, J = 14.25 Hz, 1C), 126.74 (q, J = 274.5 Hz, 1C), 126.91, 126.80, 123.12 (d, J = 3.75 Hz, 1C), 113.7 (d, J = 24.0 Hz, 1C), 57.92, 41.38 (d, J = 4.5 Hz, 1C), 30.04 (d, J = 30.0Hz, 1C), 22.90. 19F NMR (CDCl3, 282MHz) δ: -116.3, -66.5. IR (KBr): 3454, 334, 3286, 2952, 1705, 1432, 1325, 1260, 1167, 1084, 828 cm-1. Elemental analysis: Calculated values C20H17ClF4N4O4S: C, 46.11; H, 3.29; N, 10.71; S, 6.15; F, 14.58; Cl, 6.80. Measured values: C, 46.06; H, 3.24; N, 10.71; S, 6.25; F, 14.60; Cl, 6.88.

target

γ-secretase

storage

Store at +4°C

References

[1] gillman kw, starrett je jr, parker mf, xie k, bronson jj, marcin lr, mcelhone ke, bergstrom cp, mate ra, williams r, meredith je jr, burton cr, barten dm, toyn jh, roberts sb, lentz ka, houston jg, zaczek r, albright cf, decicco cp, macor je, olson re. discovery and evaluation of bms-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. acs med chem lett. 2010 mar 22;1(3):120-4.