A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.
High-resolution X-ray structures of the complexes of
HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water
molecule which is hydrogen bonded
to both the mobile flaps of the enzyme and the two carbonyls flanking
the transition-state
mimic of the inhibitors. Using the structure−activity
relationships of C
2-symmetric diol
inhibitors, computed-aided drug design tools, and first principles, we
designed and synthesized
a novel class of cyclic ureas that incorporates this structural water
and preorganizes the side
chain residues into optimum binding conformations. Conformational
analysis suggested a
preference for pseudodiaxial benzylic and pseudodiequatorial hydroxyl
substituents and an
enantiomeric preference for the RSSR stereochemistry.
The X-ray and solution NMR structure
of the complex of HIV-1PR and one such cyclic urea, DMP323, confirmed
the displacement of
the structural water. Additionally, the bound and “unbound”
(small-molecule X-ray) ligands
have similar conformations. The high degree of preorganization,
the complementarity, and
the entropic gain of water displacement are proposed to explain the
high affinity of these small
molecules for the enzyme. The small size probably contributes to
the observed good oral
bioavailability in animals. Extensive structure-based optimization
of the side chains that fill
the S2 and S2‘ pockets of the enzyme resulted in DMP323, which was
studied in phase I clinical
trials but found to suffer from variable pharmacokinetics in man.
This report details the
synthesis, conformational analysis, structure−activity relationships,
and molecular recognition
of this series of C
2-symmetry HIV-1PR
inhibitors. An initial series of cyclic ureas
containing
nonsymmetric P2/P2‘ is also discussed.
Protease inhibitors are another class of compounds for treatment of human immunodeficiency virus (E1IV)-caused diease. The emergence of resitance to the current antl-HIV drugs makes the determination of potential resistance to protease inhibitors imperative. Here we describe the isolation of an HIV type 1 (HIV-1) resistant to an IHV-protease inhibitor.Serial passage of HIV-1 (strain RF) in the presence of the inhibitor, [2-pyridylacetylisoleucylphenylalanyl-4(CHOH)J2 (P9941), failed to yield a stock of virus with a r t phenotype. However, variants of the virus with 6-to 8-fold reduced sensitivity to P9941 were selcted by using a combination ofplaque assay and endpoint titration. Genetic analysis and computer modeing of the variant proteases revealed a single change in the codon for amino acid 82 (Val -) Ala), which resulted in a protease with lower affinity and reduced sensitivity to this inhibitor and certain, but not all, related inhibitors.
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