Journal of Medicinal Chemistry p. 1177 - 1188 (1994)
Update date:2022-08-05
Topics:
Ghosh, Arun K.
Lee, Hee Yoon
Thompson, Wayne J.
Culberson, Chris
Holloway, M. Katharine
et al.
Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in vitro potency of these inhibitors. Furthermore, introduction of a small 2-alkyl group cis to the 3-hydroxyl group of either heterocyclic system further enhanced enzyme affinity. The cis-2-isopropyl group thus far offered optimum enhancement of the inhibitory properties. This led to the discovery of inhibitor 43 (IC50 3.5 nM, CIC95 50+/-14 nM) of comparable in vitro antiviral potency to the current clinical candidate 1 (Ro 31-8959) but of reduced molecular weight due to the exclusion of the P3 quinoline ligand. Also, it has been demonstrated that the octahydropyrindene derivative 34 is an effective replacement of the P1' decahydroisoquinoline derivative.
View MoreContact:+86-15995924277
Address:WuZhongOu suzhou new south road 89
Contact:86-575-86132822,86-575-86085355
Address:No.418 Dadao West Road,Qixing Street,Xinchang, Zhejiang Province, China.
Shenyang Mole pharmaceutical Technology Development Co.,Ltd
Contact:+86-24-31204918/13889278616
Address:No.44, wanliutang road, shenhe District of Shenyang
Hubei Danao Pharmaceutical Co.,Ltd.
website:http://www.danaopharm.com
Contact:+86-719-5251167
Address:Fandan Road,Danjiangkou,Hubei
GuangZhe ANFA chemical co.,Ltd
Contact:86-579-87262335
Address:Guangzhe industrial area ,shaowu city ,Fujiang
Doi:10.1080/10426509708043563
(1997)Doi:10.14233/ajchem.2014.15501
(2014)Doi:10.1007/BF00811283
(1987)Doi:10.1016/S0008-6215(03)00377-X
(2003)Doi:10.1016/j.jinorgbio.2012.04.022
(2012)Doi:10.1021/jo00114a059
(1995)