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Discovery of 2-(3,5-difluoro-4-methylsulfonaminophenyl)propanamides as potent TRPV1 antagonists
Kim, Changhoon,Ann, Jihyae,Lee, Sunho,Sun, Wei,Blumberg, Peter M.,Frank-Foltyn, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jeewoo Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.14
<P><B>Abstract</B></P> <P>A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl) propanamide <B>1</B> were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1 activation by capsaicin. The most potent antagonist <B>6</B> not only exhibited potent antagonism of activation of <I>h</I>TRPV1 by capsaicin, low pH and elevated temperature but also displayed highly potent antagonism of activation of <I>r</I>TRPV1 by capsaicin. Further studies demonstrated that antagonist <B>6</B> blocked the hypothermic effect of capsaicin <I>in vivo</I>, consistent with its <I>in vitro</I> mechanism, and it showed promising analgesic activity in the formalin animal model.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl)propanamide were investigated as TRPV1 antagonists. </LI> <LI> Compound <B>6</B> showed highly potent antagonism toward capsaicin activation. </LI> <LI> Compound <B>6</B> displayed anti-hypothermic effect and promising analgesic activity <I>in vivo</I>. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Kim, Changhoon,Ann, Jihyae,Lee, Sunho,Kim, Eunhye,Choi, Sun,Blumberg, Peter M.,Frank-Foltyn, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jeewoo Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.15
<P><B>Abstract</B></P> <P>A series of 2-(3,5-substituted 4-aminophenyl)acetamide and propanamide derivatives were investigated as human TRPV1 antagonists. The analysis of the structure-activity relationship indicated that 2-(3,5-dihalo 4-aminophenyl)acetamide analogues displayed excellent antagonism of <I>h</I>TRPV1 activation by capsaicin and showed improved potency compared to the corresponding propanamides. The most potent antagonist (<B>36</B>) exhibited potent and selective antagonism for <I>h</I>TRPV1 not only to capsaicin but also to NADA and elevated temperature; however, it only displayed weak antagonism to low pH. Further studies indicated that oral administration of antagonist <B>36</B> blocked the hypothermic effect of capsaicin <I>in vivo</I> but demonstrated hyperthermia at that dose. A docking study of <B>36</B> was performed in our established <I>h</I>TRPV1 homology model to understand its binding interactions with the receptor and to compare with that of previous antagonist <B>1</B>.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Pearce, Larry V.,Ann, Jihyae,Jung, Aeran,Thorat, Shivaji A.,Herold, Brienna K. A.,Habtemichael, Amelework D.,Blumberg, Peter M.,Lee, Jeewoo American Chemical Society 2017 Journal of medicinal chemistry Vol.60 No.19
<P>Transient receptor potential vanilloid 1 (TRPV1) has emerged as a promising therapeutic target. While radiolabeled resiniferatoxin (RTX) has provided a powerful tool for characterization of vanilloid binding to TRPV1, TRPV1 shows 20-fold weaker binding to the human TRPV1 than to the rodent TRPV1. We now describe a tritium radiolabeled synthetic vanilloid antagonist, 1-((2-(4-(methyl-[<SUP>3</SUP>H])piperidin-1-yl-4-[<SUP>3</SUP>H])-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4-dihydro-2<I>H</I>-benzo[<I>b</I>][1,4]oxazin-8-yl)urea ([<SUP>3</SUP>H]MPOU), that embodies improved absolute affinity for human TRPV1 and improved synthetic accessibility.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2017/jmcmar.2017.60.issue-19/acs.jmedchem.7b00859/production/images/medium/jm-2017-008593_0010.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm7b00859'>ACS Electronic Supporting Info</A></P>
( Larry V. Pearce ),( Jihyae Ann ),( Peter M. Blumberg ),( Jeewoo Lee ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.5
The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.
Lee, Sunho,Kim, Changhoon,Ann, Jihyae,Thorat, Shivaji A.,Kim, Eunhye,Park, Jongmi,Choi, Sun,Blumberg, Peter M.,Frank-Foltyn, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jee Pergamon Press 2017 Bioorganic & medicinal chemistry letters Vol.27 No.18
<P><B>Abstract</B></P> <P>A series of 1-substituted 3-(<I>t</I>-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for <I>h</I>TRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the <I>S</I>-configuration, providing exceptionally potent antagonists <B>13<I>S</I> </B> and <B>16<I>S</I> </B> with <I>K<SUB>i(CAP)</SUB> </I> =0.1nM. Particularly significant, <B>13<I>S</I> </B> exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for <I>r</I>TRPV1, blocking <I>in vivo</I> the hypothermic action of capsaicin, consistent with their <I>in vitro</I> mechanism. The docking study of compounds <B>13<I>S</I> </B> and <B>16<I>S</I> </B> in our <I>h</I>TRPV1 homology model indicated that the binding modes differed somewhat, with that of <B>13<I>S</I> </B> more closely resembling that of <B>GRT12360</B>.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Kim, Ho Shin,Hoang, Van-Hai,Hong, Mannkyu,Chul Kim, Kyung,Ann, Jihyae,Nguyen, Cong-Truong,Seo, Ji Hae,Choi, Hoon,Yong Kim, Jun,Kim, Kyu-Won,Sub Byun, Woong,Lee, Sangkook,Lee, Seungbeom,Suh, Young-Ger Elsevier 2019 Bioorganic & medicinal chemistry Vol.27 No.7
<P><B>Abstract</B></P> <P>On the basis of deguelin, a series of the B,C-ring truncated surrogates with <I>N</I>-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound <B>57</B> showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound <B>57</B> downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of <B>57</B> demonstrated that <B>57</B> bound well to the C-terminal ATP-binding pocket in the open conformation of the <I>h</I>HSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound <B>57</B> is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Shin, Jae-Yeon,Kong, Sun-Young,Yoon, Hye Jin,Ann, Jihyae,Lee, Jeewoo,Kim, Hyun-Jung The Korean Society of Applied Pharmacology 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.4
P7C3 and its derivatives, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol (1) and N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-methylbenzenesulfonamide (2), were previously reported to increase neurogenesis in rat neural stem cells (NSCs). Although P7C3 is known to increase neurogenesis by protecting newborn neurons, it is not known whether its derivatives also have protective effects to increase neurogenesis. In the current study, we examined how 1 induces neurogenesis. The treatment of 1 in NSCs increased numbers of cells in the absence of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), while not affecting those in the presence of growth factors. Compound 1 did not induce astrocytogenesis during NSC differentiation. 5-Bromo-2'-deoxyuridine (BrdU) pulsing experiments showed that 1 significantly enhanced BrdU-positive neurons. Taken together, our data suggest that 1 promotes neurogenesis by the induction of final cell division during NSC differentiation.
Yoon, Suyoung,Kim, Jong Hyun,Koh, Yura,Tran, Phuong-Thao,Ann, Jihyae,Yoon, Ina,Jang, Jayun,Kim, Won Kyung,Lee, Sangkook,Lee, Jiyoun,Kim, Sunghoon,Lee, Jeewoo Elsevier 2017 Bioorganic & medicinal chemistry Vol.25 No.15
<P><B>Abstract</B></P> <P>Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (<B>1</B>) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a <I>N</I>-(3,4-dimethoxybenzyl)benzenesulfonamide (<B>2a</B>) or a <I>N</I>-(2-phenoxyethyl)benzenesulfonamide groups (<B>2b</B>) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers. Among these simplified analogues, compound <B>16</B> and its constrained analogue <B>22</B> effectively inhibited S6K phosphorylation in a dose-dependent manner and exhibited cancer cell specific cytotoxicity against six different types of cancer cells. This result supports that LRS is a viable target for novel anticancer therapy.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
The SAR analysis of TRPV1 agonists with the α-methylated B-region
Cho, Yongsung,Kim, Myeong Seop,Kim, Ho Shin,Ann, Jihyae,Lee, Jiyoun,Pearce, Larry V.,Pavlyukovets, Vladimir A.,Morgan, Matthew A.,Blumberg, Peter M.,Lee, Jeewoo Elsevier 2012 Bioorganic & medicinal chemistry letters Vol.22 No.16
<P>A series of TRPV1 agonists with amide, reverse amide, and thiourea groups in the B-region and their corresponding α-methylated analogues were investigated. Whereas the α-methylation of the amide B-region enhanced the binding affinities and potencies as agonists, that of the reverse amide and thiourea led to a reduction in receptor affinity. The analysis indicated that proper hydrogen bonding as well as steric effects in the B-region are critical for receptor binding.</P>
Ha, Hee-Jin,Kang, Dong Wook,Kim, Hyuk-Min,Kang, Jin-Mi,Ann, Jihyae,Hyun, Hyae Jung,Lee, Joon Hwan,Kim, Sae Hee,Kim, Hee,Choi, Kwanghyun,Hong, Hyun-Seok,Kim, YoungHo,Jo, Dong-Gyu,Lee, Jiyoun,Lee, Jeewo American Chemical Society 2018 Journal of medicinal chemistry Vol.61 No.1
<P>We developed an orally active and blood–brain-barrier-permeable benzofuran analogue (<B>8</B>, MDR-1339) with potent antiaggregation activity. Compound <B>8</B> restored cellular viability from Aβ-induced cytotoxicity but also improved the learning and memory function of AD model mice by reducing the Aβ aggregates in the brains. Given the high bioavailability and brain permeability demonstrated in our pharmacokinetic studies, <B>8</B> will provide a novel scaffold for an Aβ-aggregation inhibitor that may offer an alternative treatment for AD.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2018/jmcmar.2018.61.issue-1/acs.jmedchem.7b00844/production/images/medium/jm-2017-00844u_0010.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm7b00844'>ACS Electronic Supporting Info</A></P>