kni-727 and 3-amino-2-hydroxy-4-phenylbutanoic-acid

kni-727 has been researched along with 3-amino-2-hydroxy-4-phenylbutanoic-acid* in 3 studies

Other Studies

3 other study(ies) available for kni-727 and 3-amino-2-hydroxy-4-phenylbutanoic-acid

ArticleYear
Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket.
    Journal of medicinal chemistry, 2009, Dec-10, Volume: 52, Issue:23

    A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P(2)' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate 1 (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of an anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity. X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group at P(2)' position revealed hydrophobic interactions with Ala28, Ile84, and Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.

    Topics: Cell Line; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Models, Molecular; Molecular Conformation; Phenylbutyrates; Structure-Activity Relationship; Substrate Specificity

2009
Identification and characterization of allophenylnorstatine-based inhibitors of plasmepsin II, an antimalarial target.
    Biochemistry, 2002, Feb-19, Volume: 41, Issue:7

    Plasmepsin II is a key enzyme in the life cycle of the Plasmodium parasites responsible for malaria, a disease that afflicts more than 300 million individuals annually. Since plasmepsin II inhibition leads to starvation of the parasite, it has been acknowledged as an important target for the development of new antimalarials. In this paper, we identify and characterize high-affinity inhibitors of plasmepsin II based upon the allophenylnorstatine scaffold. The best compound, KNI-727, inhibits plasmepsin II with a K(i) of 70 nM and a 22-fold selectivity with respect to the highly homologous human enzyme cathepsin D. KNI-727 binds to plasmepsin II in a process favored both enthalpically and entropically. At 25 degrees C, the binding enthalpy (DeltaH) is -4.4 kcal/mol and the entropic contribution (-TDeltaS) to the Gibbs energy is -5.56 kcal/mol. Structural stability measurements of plasmepsin II were also utilized to characterize inhibitor binding. High-sensitivity differential scanning calorimetry experiments performed in the absence of inhibitors indicate that, at pH 4.0, plasmepsin II undergoes thermal denaturation at 63.3 degrees C. The structural stability of the enzyme increases with inhibitor concentration in a manner for which the binding energetics of the inhibitor can quantitatively account. The effectiveness of the best compounds in killing the malaria parasite was validated by performing cytotoxicity assays in red blood cells infected with Plasmodium falciparum. EC50s ranging between 6 and 10 microM (3-6 microg/mL) were obtained. These experiments demonstrate the viability of the allophenylnorstatine scaffold in the design of powerful and selective plasmepsin inhibitors.

    Topics: Amides; Animals; Antimalarials; Aspartic Acid Endopeptidases; Binding Sites; Chromogenic Compounds; Enzyme Stability; Erythrocytes; Humans; Models, Molecular; Phenylbutyrates; Plasmodium falciparum; Protease Inhibitors; Protozoan Proteins; Substrate Specificity; Thermodynamics; Thiazoles

2002
Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine.
    Journal of medicinal chemistry, 1999, May-20, Volume: 42, Issue:10

    We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure-activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to the delineation of a set of structural charateristics that appear to afford an orally available HIV protease inhibitor. Optimum structures, exemplified by 21f (JE-2147), incorporated 3-hydroxy-2-methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl-1,3-thiazolidine-4-carbonyl (Dmt) residue at the P1' site, and 2-methylbenzylcarboxamide group as the P2' ligand. The present study demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.

    Topics: Administration, Oral; Animals; Biological Availability; Cell Line; Dipeptides; Dogs; Drug Evaluation, Preclinical; HIV Protease Inhibitors; HIV-1; Inhibitory Concentration 50; Injections, Intravenous; Oligopeptides; Phenylbutyrates; Rats; Structure-Activity Relationship; Thiazoles; Thiazolidines

1999