- Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents
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A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.
- Priebbenow, Daniel L.,Leaver, David J.,Nguyen, Nghi,Cleary, Benjamin,Lagiakos, H. Rachel,Sanchez, Julie,Xue, Lian,Huang, Fei,Sun, Yuxin,Mujumdar, Prashant,Mudududdla, Ramesh,Varghese, Swapna,Teguh, Silvia,Charman, Susan A.,White, Karen L.,Shackleford, David M.,Katneni, Kasiram,Cuellar, Matthew,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Street, Ian P.,Monahan, Brendon J.,Jarman, Kate E.,Jousset Sabroux, Helene,Falk, Hendrik,Chung, Matthew C.,Hermans, Stefan J.,Downer, Natalie L.,Parker, Michael W.,Voss, Anne K.,Thomas, Tim,Baell, Jonathan B.
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p. 4655 - 4684
(2020/06/08)
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- ARYL SULFONOHYDRAZIDES
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Compound of formula (I) wherein A is selected from (i), where RF1 is H or F; (ii); (iii) a N-containing C6 heteroaryl group; and B is (B), where X1 is either CRF2 or N, where RF2 is H or F; X2 is either CR3 or N, where R3 is selected from H, Me, CI, F OMe; X3 is either CH or N; X4 is either CRF3 or N, where RF3 is H or F; where only one or two of X1, X2, X3 and X4 may be N; and R4 is selected from I, optionally substituted phenyl, optionally substituted C5-6 heteroaryl; optionally substituted C1-6 aIkyI and optionally substituted C1-6 alkoxy, which are useful in the treatment of a condition ameliorated by the inhibition of MOZ.
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Page/Page column 40; 47
(2016/12/26)
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- Application of a Parallel Synthetic Strategy in the Discovery of Biaryl Acyl Sulfonamides as Efficient and Selective NaV1.7 Inhibitors
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The majority of potent and selective hNaV1.7 inhibitors possess common pharmacophoric features that include a heteroaryl sulfonamide headgroup and a lipophilic aromatic tail group. Recently, reports of similar aromatic tail groups in combination with an acyl sulfonamide headgroup have emerged, with the acyl sulfonamide bestowing levels of selectivity over hNaV1.5 comparable to the heteroaryl sulfonamide. Beginning with commercially available carboxylic acids that met selected pharmacophoric requirements in the lipophilic tail, a parallel synthetic approach was applied to rapidly generate the derived acyl sulfonamides. A biaryl acyl sulfonamide hit from this library was elaborated, optimizing for potency and selectivity with attention to physicochemical properties. The resulting novel leads are potent, ligand and lipophilic efficient, and selective over hNaV1.5. Representative lead 36 demonstrates selectivity over other human NaV isoforms and good pharmacokinetics in rodents. The biaryl acyl sulfonamides reported herein may also offer ADME advantages over known heteroaryl sulfonamide inhibitors.
- DiMauro, Erin F.,Altmann, Stephen,Berry, Loren M.,Bregman, Howard,Chakka, Nagasree,Chu-Moyer, Margaret,Bojic, Elma Feric,Foti, Robert S.,Fremeau, Robert,Gao, Hua,Gunaydin, Hakan,Guzman-Perez, Angel,Hall, Brian E.,Huang, Hongbing,Jarosh, Michael,Kornecook, Thomas,Lee, Josie,Ligutti, Joseph,Liu, Dong,Moyer, Bryan D.,Ortuno, Daniel,Rose, Paul E.,Schenkel, Laurie B.,Taborn, Kristin,Wang, Jean,Wang, Yan,Yu, Violeta,Weiss, Matthew M.
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p. 7818 - 7839
(2016/10/12)
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- POLY (ADP-RIBOSE) POLYMERASE INHIBITOR
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Disclosed are a phthalic hydrazide (phthalazine ketone) compound, and a pharmaceutical composition comprising the same. As a DNA repair enzyme poly (ADP-ribozyme) polymerase inhibitor, the compound and the pharmaceutical composition can effectively treat diseases involving PARP enzymatic activity, including cancer, neural degenerative diseases, inflammation and the like.
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Paragraph 0091; 0062
(2015/02/25)
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- BIARYL ACYL-SULFONAMIDE COMPOUNDS AS SODIUM CHANNEL INHIBITORS
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The present invention provides compounds of Formula (Ia), and pharmaceutically acceptable salts thereof. The compounds are useful as inhibitors of voltage-gated sodium channels, in particular Nav 1.7. (Ia); as described in the specification. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention, as well as intermediates and processes useful for making the compounds.
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Paragraph 00248
(2015/04/22)
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- POLY (ADP-RIBOSE) POLYMERASE INHIBITOR
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Disclosed are a phthalic hydrazide (phthalazine ketone) compound, and a pharmaceutical composition comprising the same. As a DNA repair enzyme poly (ADP-ribozyme) polymerase inhibitor, the compound and the pharmaceutical composition can effectively treat diseases involving PARP enzymatic activity, including cancer, neural degenerative diseases, inflammation and the like.
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Paragraph 0051; 0065; 0066
(2014/11/13)
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- MULTI-CYCLIC COMPOUNDS AND METHODS OF USE
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The present invention relates to compounds of Formulas I and II, wherein B1, B2, B3, B4, C1, C2, ring D, L1, L2 and R1-4 are defined herein, synthetic inter
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Page/Page column 34
(2008/12/05)
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- Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor
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Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenes
- Hodous, Brian L.,Geuns-Meyer, Stephanie D.,Hughes, Paul E.,Albrecht, Brian K.,Bellon, Steve,Bready, James,Caenepeel, Sean,Cee, Victor J.,Chaffee, Stuart C.,Coxon, Angela,Emery, Maurice,Fretland, Jenne,Gallant, Paul,Gu, Yan,Hoffman, Doug,Johnson, Rebecca E.,Kendall, Richard,Kim, Joseph L.,Long, Alexander M.,Morrison, Michael,Olivieri, Philip R.,Patel, Vinod F.,Polverino, Anthony,Rose, Paul,Tempest, Paul,Wang, Ling,Whittington, Douglas A.,Zhao, Huilin
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p. 611 - 626
(2007/10/03)
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- PROTEIN KINASE MODULATORS AND METHOD OF USE
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The present invention relates to chemical compounds having a general formula I wherein A, B, D, E, G, H1-5 and R1-4 are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of these kinases. For example, the compounds are capable of modulating kinase enzymes thereby influencing the process of angiogenesis and treating angiogenesis-related diseases and other poliferative disorders, including cancer and inflammation. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of protein kinases.
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Page/Page column 117
(2010/02/14)
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- Fluorophenols and (trifluoromethyl)phenols as substrates of site-selective metalation reactions: To protect or not to protect
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O-Methoxymethyl (MOM) protected fluorophenols can be cleanly metalated and subsequently be submitted to site-selective electrophilic substitution. The 2- and 4-isomers exhibit ambivalent reactivity: deprotonation occurs at the position adjacent to the oxygen when butyllithium is employed whereas the position adjacent to the fluorine is attacked by the superbasic mixture of butyllithium and potassium tert-butoxide (LIC-KOR). The MOM-protected (trifluoromethyl)-phenols react exclusively at oxygen-neighboring positions. The meta isomer provides another example of optional site selectivity, undergoing hydrogen/metal exchange at the 2-position with the LIC-KOR reagent and at the 6-position with sec-butyllithium. Unprotected (trifluoromethyl)phenols can also be ortho-metalated after O-deprotonation, although the products are formed in only moderate yields.
- Marzi, Elena,Mongin, Florence,Spitaleri, Andrea,Schlosser, Manfred
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p. 2911 - 2915
(2007/10/03)
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- NEW COMPOUNDS
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The present invention relates to novel derivatives of 3-hydroxyanthranilic acid, 3-HANA, of the general formula I wherein R1 and R2 are the same or different and selected from H, alkyl, aryl and arylalkyl; X and Y are the same or different and selected fr
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