J. Yuan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4836–4843
4843
Scheme 5. Synthesis of 7a. Reagents and conditions: (a) NaBH4, CH3OH, rt, 2 h; (b) BrCH2CO2Et, NaH, THF, 0 °C to reflux, 12 h; (c) NaBH4, CH3CH2OH, rt, 16 h; (d) MsCl, Et3N,
CH2Cl2, 0 °C to rt, 1 h; (e) NaN3, DMF, 80 °C, 5 h; (f) Pd–C, H2, CH3OH, rt, 16 h; (g) preparative HPLC; (h) MeOCOCl, DMAP, Et3N, CH2Cl2; (i) 1:1 2 M aq HCl/MeCN, rt, 16 h; (j)
(1S,3R,4S)-33b, HOBt, HBTU, i-Pr2NEt, DMF, rt, 5 min.
14. Tice, C. M.; Xu, Z.; Yuan, J.; Simpson, R. D.; Cacatian, S. T.; Flaherty, P. T.; Zhao,
crystallography. This effort culminated in the discovery of 8d, a po-
tent, selective and orally bioavailable inhibitor of renin which
effectively lowered blood pressure in an animal model of human
hypertension.
W.; Guo, J.; Ishchenko, A.; Singh, S. B.; Wu, Z.; Scott, B. B.; Bukhtiyarov, Y.;
Berbaum, J.; Mason, J.; Panemangalore, R.; Cappiello, M. G.; Mueller, D.;
Harrison, R. K.; McGeehan, G. M.; Dillard, L. W.; Baldwin, J. J.; Claremon, D. A.
Bioorg. Med. Chem. Lett. 2009, 19, 3541.
15. Sham, H. L.; Rempel, C. A.; Stein, H.; Cohen, J. J. Chem. Soc., Chem. Commun.
1987, 683.
16. Evolution of diverse classes of renin inhibitors through the years Tice, C. M.;
Singh, S. B. In Aspartic Acid Proteases as Therapeutic Targets; Ghosh, A., Ed.;
Wiley-VCH, 2010; vol. 45, p 297.
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23. Compound 8d gave the following spectral data: 1H NMR (400 MHz, CD3OD) d
7.69–7.66 (m, 1H), 7.30–7.12 (m, 4H), 6.88–6.84 (m, 2H), 6.59 (s, 2H), 4.23–
4.12 (m, 2H), 3.75–3.57 (m, 2H), 3.43–3.33 (m, 1H), 3.27–3.00 (m, 9H), 2.75–
2.54 (m, 3H), 2.23–1.79 (m, 3H), 1.68–1.12 (m, 9H), 0.86–0.75 (m, 1H); MS ESI
+ve ionization, m/z 545, 547 (M+H+).