There's tons out there about KNI-272 and derivatives, including some work that has previously crossed radar. Nothing on KNI-764, but the big number inspires confidence. :-)
There has been TONS of preclinical work done with KNI-272. Getting closer.......
Chem Pharm Bull (Tokyo) 1998 May;46(5):867-870
Synthesis of dipeptide-type human immunodeficiency virus (HIV) protease
inhibitors with a binding unit to GP120.
Asagarasu A, Takayanagi N, Achiwa K
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
[Medline record in process]
Some dipeptide-type human immunodeficiency virus (HIV) protease inhibitors derived from KNI-102, with a
N-carbomethoxycarbonylprolyl-phenylalanine benzyl ester (CPF) moiety as a binding site to gp120, were synthesized.
Compounds 11a showed 7--100 times higher HIV protease-inhibitory activity (11a; IC50 = 0.90 microgram/ml, 1.1 microM)
than the standard compound 3 or 4 (3; IC50 = 3.7 micrograms/ml, 7.7 microM, 4; IC50 = 75 micrograms/ml, 155 microM).
Generally, the compounds substituted at the o-position of the phenoxyacetyl group 7a, 11a, 16a and 21a showed several times
higher inhibitory activity than 3.
PMID: 9621421, UI: 98284441
Chem Pharm Bull (Tokyo) 1998 Apr;46(4):697-703
Syntheses of HIV-protease inhibitors having a peptide moiety which binds
to GP120.
Asagarasu A, Uchiyama T, Achiwa K
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Some HIV-protease inhibitor derivatives having an N-carbomethoxycarbonyl-prolyl-phenylalanine benzyl ester (CPF) moiety
as a binding site to gp120 were designed and synthesized. Almost all the compounds bearing CPF on the phenoxyacetyl group
showed protease-inhibitory activity. Compounds 25a and 25b, which have the CPF moiety at the ortho- and meta-positions of
the phenoxyacetyl group, respectively, had anti-HIV activity, although the others showed only protease-inhibitory activity.
These results suggest that 25b binds to gp120 and inhibits HIV protease.
PMID: 9579045, UI: 98240208
Arch Pharm (Weinheim) 1998 Mar;331(3):87-89
KNI-577, a potent small-sized HIV protease inhibitor based on the
dipeptide containing the hydroxymethylcarbonyl isostere as an ideal
transition-state mimic.
Kiso Y, Yamaguchi S, Matsumoto H, Mimoto T, Kato R, Nojima S, Takaku H, Fukazawa T, Kimura T, Akaji K
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Japan.
PMID: 9557134, UI: 98217882
Biopharm Drug Dispos 1996 Dec;17(9):739-751
Binding characteristics of KNI-272 to plasma proteins, a new potent
tripeptide HIV protease inhibitor.
Kiriyama A, Nishiura T, Ishino M, Yamamoto Y, Ogita I, Kiso Y, Takada K
Department of Pharmaceutics and Pharmacokinetics, Kyoto Pharmaceutical University, Japan.
The binding characteristics of KNI-272, a potent and selective human immunodeficiency virus (HIV) protease inhibitor, were
evaluated in rat and human plasma, and in solutions of human alpha 1-acid glycoprotein (AAG) and human serum albumin
(HSA). The unbound fractions (Fu) of KNI-272 were 12.13 and 2.24% in rat and human plasma, respectively, at the drug
concentration of 1.0 microgram mL-1. Although KNI-272 binds to both AAG and HSA, the Fu of KNI-272 in AAG solution
was 1.83%, and only one-quarter of that in HSA solution (Fu = 6.78%). Binding displacing agents, such as disopyramide,
warfarin, diazepam, and digitoxin, were used to determine the binding site of KNI-272 on these plasma proteins. The Fu of
KNI-272 in AAG solution increased 14-fold when disopyramide was added to the AAG solution. In addition, warfarin,
diazepam, and digitoxin were added to HSA solution as representative drugs bound to distinct binding sites on HSA, namely
sites I, II, and III, respectively. The Fu values of KNI-272 in HSA solution significantly increased when warfarin and diazepam
were added. In particular, with the addition of warfarin to HSA solution, the Fu of KNI-272 increased to 16%. The modified
Scatchard plots of KNI-272 binding to AAG and HSA both showed biphasic curves, and the KNI-272 binding sites at low
concentration range on AAG and HSA disappeared with the addition of disopyramide and warfarin, respectively. Therefore, it
is considered that KNI-272 binds to the identical site as disopyramide on AAG and site I on HSA in the low KNI-272
concentration range. By comparing the KNI-272 binding parameters obtained in human plasma and these protein solutions, we
can assume that KNI-272 binding at low concentration in human plasma is mainly concerned with the binding on AAG. As
KNI-272 concentration in plasma increases, HSA becomes concerned with KNI-272 binding.
PMID: 8968527, UI: 97123278
Bioorg Med Chem 1996 Sep;4(9):1565-1572
Solution conformations of KNI-272, a tripeptide HIV protease inhibitor
designed on the basis of substrate transition state: determined by NMR
spectroscopy and simulated annealing calculations.
Ohno Y, Kiso Y, Kobayashi Y
Institute for Protein Research, Osaka University, Japan.
KNI-272, a highly selective and potent HIV protease inhibitor containing allophenylnorstatine
[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], named Apns, has been studied in dimethylsulfoxide-d6 by NMR
spectroscopy and simulated annealing calculations. 1H and 13C spectra showed the presence of two conformers characterized
by the configuration of the imide bond between the Apns and Thz residues, i.e., trans and cis forms, respectively. Rotating
frame Overhauser effect spectra revealed that the trans conformer is dominant. The solution structure calculated from the
distance information resulting from nuclear Overhauser effects experiments is similar overall to those observed in the solid
states, either as a single crystal or as complex with the protease. The results from both molecular dynamics simulations and
experimental 13C longitudinal relaxation times indicate that the backbone of KNI-272 has a fairly rigid conformation.
PMID: 8894113, UI: 97049383 |
