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BRD2879

BRD-K56962879-001-01-5
CAS 1304750-47-7
Chemical Formula: C30H38FN3O5S
Molecular Weight: 571.7084

3-cyclohexyl-1-(((4R,5R)-8-((3-fluorophenyl)ethynyl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-1-methylurea

3-cyclohexyl-1-[[(4R,5R)-8-[2-(3-fluorophenyl)ethynyl]-2-[(2S)-1-hydroxypropan-2-yl]-4-methyl-1,1-dioxo-4,5-dihydro-3H-6,1$l^{6},2-benzoxathiazocin-5-yl]methyl]-1-methylurea

BRD2879 is a potent and cell-active inhibitor of IDH1-R132H with a markedly different structure from previously reported probes with (IC50 = 50 nM for inhibiting IDH1-R132H enzyme). BRD2879 represents a new structural class of mutant IDH1 inhibitors that, with optimization, may prove useful in the study of this enzyme and its role in cancer

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The Eli and Edythe L. Broad Institute of MIT and Harvard (/ˈbrd/), often referred to as the Broad Institute, is a biomedical and genomic research center located in Cambridge, Massachusetts, United States. The institute is independently governed and supported as a 501(c)(3) nonprofit research organization under the name Broad Institute Inc.,[1][2] and is partners with Massachusetts Institute of Technology, Harvard University, and the five Harvard teaching hospitals.

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Mahmud Hussain

Mahmud M. Hussain

Harvard University
Cambridge, MA, United States

PAPER

Abstract Image

Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
§ Howard Hughes Medical Institute, Cambridge, Massachusetts 02138, United States
Department of Neurological Surgery, Washington Univeristy School of Medicine, St. Louis, Missouri 63110, United States
ACS Med. Chem. Lett., 2016, 7 (10), pp 944–949
DOI: 10.1021/acsmedchemlett.6b00264
Publication Date (Web): August 18, 2016
Copyright © 2016 American Chemical Society

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1H NMR (300 MHz, CDCl3, 27 °C) δ 7.88 (d, J = 8.3 Hz, 1H), 7.39-7.27 (m, 3H), 7.22-7.14 (m, 2H), 7.12-7.03 (m, 1H), 4.57 (td, J = 9.5, 2.5 Hz, 1H), 4.35-4.23 (m, 2H), 3.97-3.78 (m, 2H), 3.74-3.60 (m, 2H), 3.51 (ddd, J = 12.3, 9.9, 4.0 Hz, 1H), 3.40 (dd, J = 15.8, 5.1 Hz, 1H), 3.18 (dd, J = 9.9, 2.9 Hz, 1H), 3.12 (dd, J = 14.4, 2.6 Hz, 1H), 2.66 (s, 3H), 2.30-2.16 (m, 1H), 2.06 (d, J = 12.2 Hz, 1H), 1.96 (d, J = 12.1 Hz, 1H), 1.69-1.58 (m,1H), 1.58-1.45 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H), 1.40-0.97 (m, 5H), 0.94 (d, J = 7.0 Hz, 3H).

13C NMR (75 MHz, CDCl3, 27 °C) δ 164.20, 160.92, 157.74, 154.80, 134.60, 130.26, 130.15, 129.56, 128.62, 127.82, 127.77, 127.68, 126.90, 124.27, 118.81, 118.50, 116.63, 116.35, 91.32, 88.40, 85.60, 64.86, 58.03, 51.64, 49.88, 48.51, 36.73, 34.51, 34.35, 34.31, 25.72, 25.28, 25.23, 15.76, 15.05.

HRMS (ESI) calc’d for C30H38FN3O5S [M+H]+ : 572.2589. Found: 572.2588.

1H NMR PREDICT

13C NMR PREDICT

REFERENCES

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1
Jason M. Law, Sebastian C. Stark, Ke Liu, Norah E. Liang, Mahmud M. Hussain, Matthias Leiendecker, Daisuke Ito, Oscar Verho, Andrew M. Stern, Stephen E. Johnston, Yan-Ling Zhang, Gavin P. Dunn, Alykhan F. Shamji, and Stuart L. Schreiber
Publication Date (Web): August 18, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00264

 

FC1=CC(C#CC2=CC(O[C@@H](CN(C(NC3CCCCC3)=O)C)[C@H](C)CN([C@@H](C)CO)S4(=O)=O)=C4C=C2)=CC=C1


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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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