- Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods
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The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1cat-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.
- Sarkar, Dhruba,Olejniczak, Edward T.,Phan, Jason,Coker, Jesse A.,Sai, Jiqing,Arnold, Allison,Beesetty, Yugandhar,Waterson, Alex G.,Fesik, Stephen W.
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p. 8325 - 8337
(2020/09/21)
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- Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile
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We recently described (J. Med. Chem. 2008, 51, 6538-6546) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further finetuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).
- Kazmierski, Wieslaw M.,Anderson, Don L.,Aquino, Christopher,Chauder, Brian A.,Duan, Maosheng,Ferris, Robert,Kenakin, Terrence,Koble, Cecilia S.,Lang, Dan G.,Mcintyre, Maggie S,Peckham, Jennifer,Watson, Christian,Wheelan, Pat,Spaltenstein, Andrew,Wire, Mary B.,Svolto, Angilique,Youngman, Michael
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scheme or table
p. 3756 - 3767
(2011/07/30)
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- Thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV: Structure-based drug design, synthesis, and biological evaluation
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A novel series of potent thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV was discovered using structure-based drug design. Synthesis, structure-activity relationship, and optimization of physicochemical properties are described. Low nanomolar potency was achieved, and selected compounds with improved thermodynamic solubility showed promising in vitro inhibition of carbonic anhydrase activity in rabbit iris ciliary body homogenate.
- Vernier, William,Chong, Wesley,Rewolinski, David,Greasley, Samantha,Pauly, Thomas,Shaw, Morena,Dinh, Dac,Ferre, Rose Ann,Nukui, Seiji,Ornelas, Martha,Reyner, Eric
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experimental part
p. 3307 - 3319
(2010/07/10)
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to novel compounds, compositions and combinations thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
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Page/Page column 47
(2008/12/06)
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- HETEROCYCLES USEFUL AS INHIBITORS OF CARBONIC ANHYDRASE
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Sulfonamides and pharmaceutical compositions containing the compounds useful in controlling intraocular pressure are disclosed. Methods for controlling intraocular pressure through administration of the compositions are also disclosed.
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Page/Page column 83
(2008/06/13)
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- CCR5 ANTAGONISTS AS THERAPEUTIC AGENTS
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable derivatives thereof, useful in the treatment or prophylaxis of CCR5-related diseases and disorders, for example, in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
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- Synthesis and gastroprokinetic activity of 2-Almino-N-[(4-benzyl-2-morpholinyl)methyl]benzamide derivatives
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2-Alkoxy-4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chlorobenzamides had been identified as the interesting members of a series of selective and potent gastroprokinetic agents. A new series of 2-amino- and 2-(substituted amino)-N-[(4-benzyl-2-morpholinyl)methyl]benzamides (13-35) has been synthesized and these compounds were examined to determine whether they have advantages over the 2-morpholinyl benzamides 1 with a 2-alkoxy group. The gastroprokinetic activity was generally reduced, but several compounds showed relatively:potent activity, comparable to that of the standard agent, metoclopramide. N-[(4-Benzyl-2-morpholinyl)methyl]-4-chloro-2-[(4- chlorobenzoyl)amino]benzamide (32) showed the most potent activity in this series.
- Kato,Morie,Ohno,Yoshida,Yoshida,Naruto
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p. 582 - 587
(2007/10/02)
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- Substituted benzamide derivatives, for enhancing gastrointestinal motility
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Compounds of the formula: STR1 wherein R is hydrogen, alkoxycarbonyl, benzyloxycarbonyl, heteroarylalkyl, phenylalkenyl, or --T--(Y)p --R6 (wherein T is single bond or alkylene, Y is oxygen, sulfur or carbonyl, R6 is phenyl, substituted phenyl, naphthyl, or diphenylmethyl, and p is 0 or 1, provided that when T is single bond, p is 0); R1 is halogen, hydroxy, alkoxy, cycloalkyloxy, alkenyloxy, alkynyloxy, alkoxy interrupted by oxygen or carbonyl, alkylthio, amino, monosubstituted amino, or a substituted alkoxy; R2 is hydrogen; R3 is hydrogen, halogen, amino, alkylamino, dialkylamino, alkanoylamino, or nitro; R4 is hydrogen, halogen, nitro, sulfamoyl, alkylsulfamoyl, or dialkylsulfamoyl; or any two adjacent groups of the R1, R2, R3 and R4 may combine to form alkylenedioxy, and the remaining two groups are each hydrogen; R5 is hydrogen or alkyl; X is alkylene; m and n are each 1 or 2; provided that at least one of the groups R2, R3 and R4 is other than hydrogen, and acid addition salts, quaternary ammonium salts and N-oxide derivatives thereof, processes for preparation thereof, and pharmaceutical composition containing the same. Said compounds, salts and N-oxide derivatives thereof show excellent gastrointestinal motility enhancing activity.
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