Document 0081
 DOCN  M9590081
 TI    Use of medium-sized cycloalkyl rings to enhance secondary binding:
       discovery of a new class of human immunodeficiency virus (HIV) protease
       inhibitors.
 DT    9509
 AU    Romines KR; Watenpaugh KD; Tomich PK; Howe WJ; Morris JK; Lovasz KD;
       Mulichak AM; Finzel BC; Lynn JC; Horng MM; et al; Upjohn Laboratories,
       Kalamazoo, Michigan 49001, USA.
 SO    J Med Chem. 1995 May 26;38(11):1884-91. Unique Identifier : AIDSLINE
       MED/95302407
 AB    A unique strategy for the enhancement of secondary binding of an
       inhibitor to an enzyme has been demonstrated in the design of new human
       immunodeficiency virus (HIV) protease inhibitors. When the planar
       benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800
       microM) was replaced with medium-sized (i.e., 7-9),
       conformationally-flexible, alkyl rings, the enzyme inhibitory activity
       of the resulting compounds was dramatically improved, and inhibitors
       with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were
       obtained. X-ray crystal structures of these inhibitors complexed with
       HIV protease indicated the cycloalkyl rings were able to fold into the
       S1' pocket of the enzyme and fill it much more effectively than the
       rigid benzene ring of the 4-hydroxycoumarin compound. This work has
       resulted in the identification of a promising lead structure for the
       design of potent, deliverable HIV protease inhibitors. Compound 5d, a
       small (MW = 324), nonpeptidic structure, has already shown several
       advantages over peptidic inhibitors, including high oral bioavailability
       (91-99%), a relatively long half-life (4.9 h), and ease of synthesis
       (three steps).
 DE    Animal  Antiviral Agents/*CHEMICAL SYNTHESIS/*METABOLISM/PHARMACOLOGY
       Comparative Study  Crystallography, X-Ray  HIV Protease/METABOLISM  HIV
       Protease Inhibitors/*CHEMICAL SYNTHESIS/*METABOLISM/  PHARMACOLOGY  Male
       Microbial Sensitivity Tests  Molecular Structure  Pyrans/CHEMICAL
       SYNTHESIS/METABOLISM/PHARMACOLOGY  Rats  Structure-Activity Relationship
       4-Hydroxycoumarins/*CHEMICAL SYNTHESIS/*METABOLISM/PHARMACOLOGY  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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