Li F.,Oklahoma Medical Research Foundation |
Li F.,University of Oklahoma |
Li F.,University of Texas Health Science Center at Houston |
Chvyrkova I.,Oklahoma Medical Research Foundation |
And 6 more authors.
Applied Microbiology and Biotechnology | Year: 2012
The metalloprotease activity of lethal factor (LF) from Bacillus anthracis (B. anthracis) is a main source of toxicity in the lethality of anthrax infection. Thus, the understanding of the enzymatic activity and inhibition of B. anthracis LF is of scientific and clinical interests. We have designed, synthesized, and studied a peptide inhibitor of LF, R9LF-1, with the structure NH 2-(D-Arg) 9-Val-Leu- Arg-CO-NHOH in which the C-terminal hydroxamic acid is commonly used in the inhibitors of metalloproteases to chelate the active-site zinc. This inhibitor was shown to be very stable in solution and effectively inhibited LF in kinetic assays. However, its protection on murine macrophages against lethal toxin's lysis activity was relatively weak in longer assays. We further observed that the hydroxamic acid group in R9LF-1 was hydrolyzed by LF, and the hydrolytic product of this inhibitor is considerably weaker in inhibition of potency. To resist this unique hydrolytic activity of LF, we further designed a new inhibitor R9LF-2 which contained the same structure as R9LF-1 except replacing the hydroxamic acid group with N,O-dimethyl hydroxamic acid (DMHA), -N (CH 3)-O-CH 3. R9LF-2 was not hydrolyzed by LF in longterm incubation. It has a high inhibitory potency vs. LF with an inhibition constant of 6.4 nM had a better protection of macrophages against LF toxicity than R9LF-1. These results suggest that in the development of new LF inhibitors, the stability of the chelating group should be carefully examined and that DMHA is a potentially useful moiety to be used in new LF inhibitors. © Springer-Verlag 2012.
Ghosh A.K.,Purdue University |
Ghosh A.K.,University of Illinois at Chicago |
Brindisi M.,Purdue University |
Yen Y.-C.,Purdue University |
And 15 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015
We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a-h) or a thiazole moiety (compounds 4a-e) as the P3 ligand. We have also explored Boc-β-amino-l-alanine as a novel P2 ligand. A number of inhibitors have displayed β-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki = 0.25 nM, cellular EC50 of 194 nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound β-secretase which revealed critical interactions in the active site. © 2014 Elsevier Ltd. All rights reserved.
Chang W.-P.,Oklahoma Medical Research Foundation |
Huang X.,Oklahoma Medical Research Foundation |
Downs D.,Oklahoma Medical Research Foundation |
Cirrito J.R.,University of Washington |
And 5 more authors.
FASEB Journal | Year: 2011
Alzheimer disease is intimately linked to an excess amount of amyloid-β (Aβ) in the brain. Thus, therapeutic inhibition of Aβ production is an attractive clinical approach to treat this disease. Here we provide the first direct experimental evidence that the treatment of Tg2576 transgenic mice with an inhibitor of β-secretase, GRL-8234, rescues the age-related cognitive decline. We demonstrated that the injected GRL-8234 effectively enters the brain and rapidly decreases soluble Aβ in the brain of Tg2576 mice. The rescue of cognition, which was observed only after long-term inhibitor treatment ranging from 5 to 7.5 mo, was associated with a decrease of brain amyloid-β plaque load. We also found no accumulation of amyloid-β precursor protein after several months of inhibitor treatment. These observations substantiate the idea that Aβ accumulation plays a major role in the cognitive decline of Tg2576 mice and support the concept of Aβ reduction therapy as a treatment of AD. © FASEB.
Li A.,Idaho State University |
Li A.,CoMentis Inc. |
May M.P.,Idaho State University |
Bigelow J.C.,Idaho State University
Biomedical Chromatography | Year: 2010
Dehydroepiandrosterone (DHEA) is an important neurosteroid with neuronal protection and memory enhancement functions. 7α-OH DHEA and 7β-OH DHEA are the two important metabolites of DHEA in the brain. We have developed an LC/MS method to quantitatively analyze 7α-OH DHEA and 7β-OH DHEA. Chromatographic separation was carried out on a C18 column with gradient elution using mobile phases of formic acid in acetonitrile and in water formic acid. Mass spectral detection was performed with a ThermoFinnigan LCQ advantage quadruple ion trap mass spectrometer with electrospray ionization. Positive ion chromatograms were acquired using single ion monitoring. The protonated molecule was 305 m/z, but the most abundant ion (269 m/z) was used for quantification. This method was validated and applied to investigate the 7-hydroxylation of DHEA. When incubating DHEA with rat brain microsomes, both 7α-OH DHEA and 7β-OH DHEA were observed, but 7α-OH DHEA was the major metabolite. Copyright © 2009 John Wiley & Sons, Ltd.
Campochiaro P.A.,Wilmer Eye Institute |
Shah S.M.,Wilmer Eye Institute |
Hafiz G.,Wilmer Eye Institute |
Heier J.S.,Ophthalmic Consultants of Boston |
And 11 more authors.
American Journal of Ophthalmology | Year: 2010
Purpose: Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema. Design: A multicenter phase I/II clinical trial. Methods: Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks. Results: Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine. Conclusions: This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects. © 2010 Elsevier Inc. All rights reserved.
CoMentis Inc. | Date: 2015-01-22
The present invention provides a hydrate of N-[(4S)-2-amino-2,2-dimethyldispiro[1,3-oxazole-4,4-chromene-3,3-oxetan]-6-yl]-5-chloropyridine-2-carboxamide which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing or treating diseases or conditions associated with and/or mediated by -secretase activity, hydrolysis of a -secretase site of a -amyloid precursor protein, and/or -amyloid protein accumulation, including a pharmaceutical composition for preventing or treating diseases including, but not limited to, Glaucoma, MCI (Mild cognitive impairment) or Alzheimers disease, especially, Alzheimers disease.
CoMentis Inc. and Astellas Pharma Inc. | Date: 2014-02-27
The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing or treating diseases or conditions associated with and/or mediated by -secretase activity, hydrolysis of a -secretase site of a -amyloid precursor protein, and/or -amyloid protein accumulation, including a pharmaceutical composition for preventing or treating diseases including, but not limited to, Glaucoma, MCI (Mild cognitive impairment) or Alzheimers disease, especially, Alzheimers disease.
CoMentis Inc. | Date: 2015-07-08
Provided are substituted quinuclidine compounds, pharmaceutical compositions comprising such compounds, and methods of modulating 7 nicotinic acetylcholine receptors and treating neurological disorders using such compounds.
CoMentis Inc. | Date: 2010-10-04
Described herein are novel beta-secretase inhibitors and methods for their use, including methods of treating Alzheimers disease.