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Science 21 January 1994:
Vol. 263. no. 5145, pp. 380 - 384
DOI: 10.1126/science.8278812
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Articles

Science, Vol 263, Issue 5145, 380-384
Copyright © 1994 by American Association for the Advancement of Science

articles

Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors

PY Lam, PK Jadhav, CJ Eyermann, CN Hodge, Y Ru, LT Bacheler, JL Meek, MJ Otto, MM Rayner, YN Wong, and al. et

Department of Virology Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19880.

Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.


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