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EVP 4593

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QNZ

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EVP4593; EVP 4593; EVP-4593

M.Wt 356.42 545380-34-5; QNZ (EVP4593); QNZ; 6-Amino-4-(4-phenoxyphenylethylamino)quinazoline; N4-(4-phenoxyphenethyl)quinazoline-4,6-diamine;
Formula C₂₂H₂₀N₄O
CAS No 545380-34-5

QNZ(EVP4593) is a derivative of 6-aminoquinazoline class that has been previously isolated as an inhibitor of PMA/PHA-induced NF-κB pathway activation in Jurkat cells (IC50= 9 nM).

QNZ(EVP4593) is a derivative of 6-aminoquinazoline class that has been previously isolated as an inhibitor of PMA/PHA-induced NF-κB pathway activation in Jurkat cells (IC50= 9 nM).
IC50 Value: 9 nM [1]
Target: NF-kB signaling
in vitro: The efficacy of EVP4593 was dose-dependent in the range between 100 uM and 400 uM in the fly food. The EVP4593 had no significant effect on climbing performance of HD flies at 50 ?M. The EVP4593 had no toxic effects on Drosophila in the range of concentrations tested in our assays (50 – 400 ?M) [1]. Addition of 300 nM of EVP4593 resulted in strong attenuation of SOC Ca2+ influx in YAC128 MSN neurons. On average the amplitude of SOC Ca2+ entry in YAC128 MSN was reduced from 0.30 ± 0.02 (n = 29) in the presence of DMSO control to 0.11 ± 0.02 (n = 54) in the presence of 300 nM of EVP4593 (p < 0.001).
in vivo:

Paper

Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I

Author affiliations

Abstract

By probing the quinone substrate binding site of mitochondrial complex I with a focused set of quinazoline-based compounds, we identified substitution patterns as being critical for the observed inhibition. The structure activity relationship study also resulted in the discovery of the quinazoline 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (EVP4593) as a highly potent inhibitor of the multisubunit membrane protein. EVP4593 specifically and effectively reduces the mitochondrial complex I-dependent respiration with no effect on the respiratory chain complexes II–IV. Similar to established Q-site inhibitors, EVP4593 elicits the release of reactive oxygen species at the flavin site of mitochondrial complex I. Recently, EVP4593 was nominated as a lead compound for the treatment of Huntingtons disease. Our results challenge the postulated primary mode-of-action of EVP4593 as an inhibitor of NF-κB pathway activation and/or store-operated calcium influx.

Graphical abstract: Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I
PAPER
Bioorganic & Medicinal Chemistry (2003), 11(3), 383-391.

Abstract

We disclose here a new structural class of low-molecular-weight inhibitors of NF-κB activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure–activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-κB transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-κB transcriptional activation and TNF-α production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.


Compound 11q exhibited a highly inhibitory activity toward NF-κB activation and also showed an anti-inflammatory effect.

Image for unlabelled figure
11q (72 mg, 77% yield):
mp 168–170 C;
1 H NMR (DMSO-d6) d 8.33 (br s, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.40–7.34 (m, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.20–7.07 (m, 3H), 6.98–6.92 (m, 4H), 5.59 (br s, 2H), 3.79–3.72 (m, 2H), 2.95 (t, J=7.3 Hz, 2H);
MS (TOF) m/z 357 (M + H)+; anal. calcd for C22H20N4O 1.0H2O: C, 70.57; H, 5.65; N, 14.96. Found: C, 70.48; H, 5.60; N, 14.87.
REF
Bioorganic & Medicinal Chemistry (2003), 11(18), 3869-3878.
JP 2004059454
 CN 1709259
Bioorganic & Medicinal Chemistry Letters (2009), 19(19), 5665-5669
Journal of Medicinal Chemistry (2014), 57(6), 2247-2257
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C1=CC=C(C=C1)OC2=CC=C(C=C2)CCNC3=NC=NC4=C3C=C(C=C4)N

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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