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Publisher Correction: A mass spectrometry-based proteome map of drug action in lung cancer cell lines.

Benjamin Ruprecht, Julie Di Bernardo, Zhao Wang, Xuan Mo, Oleg Ursu, Matthew Christopher, Rafael B Fernandez, Li Zheng, Brian D Dill, Huijun Wang, Yuting Xu, Andy Liaw, Jonathan D Mortison, Nirodhini Siriwardana, Brian Andresen, Meir Glick, James R Tata, Victoria Kutilek, Ivan Cornella-Taracido, An Chi,

An amendment to this paper has been published and can be accessed via a link at the top of the paper. ... Read more >>

Nat Chem Biol (Nature chemical biology)
[2020, 16(10):1149]

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A mass spectrometry-based proteome map of drug action in lung cancer cell lines.

Benjamin Ruprecht, Julie Di Bernardo, Zhao Wang, Xuan Mo, Oleg Ursu, Matthew Christopher, Rafael B Fernandez, Li Zheng, Brian D Dill, Huijun Wang, Yuting Xu, Andy Liaw, Jonathan D Mortison, Nirodhini Siriwardana, Brian Andresen, Meir Glick, James R Tata, Victoria Kutilek, Ivan Cornella-Taracido, An Chi,

Mass spectrometry-based discovery proteomics is an essential tool for the proximal readout of cellular drug action. Here, we apply a robust proteomic workflow to rapidly profile the proteomes of five lung cancer cell lines in response to more than 50 drugs. Integration of millions of quantitative protein-drug associations substantially improved ... Read more >>

Nat. Chem. Biol. (Nature chemical biology)
[2020, 16(10):1111-1119]

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From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.

Whitney L Petrilli, Gregory C Adam, Roman S Erdmann, Pravien Abeywickrema, Vijayalakshmi Agnani, Xi Ai, Jen Baysarowich, Noel Byrne, John P Caldwell, Wonsuk Chang, Edward DiNunzio, Zhe Feng, Rachael Ford, Sookhee Ha, Yongcheng Huang, Brian Hubbard, Jennifer M Johnston, Michael Kavana, Jean-Marie Lisnock, Rui Liang, Jun Lu, Zhijian Lu, Juncai Meng, Peter Orth, Oksana Palyha, Gopal Parthasarathy, Scott P Salowe, Sujata Sharma, Jennifer Shipman, Stephen M Soisson, Alison M Strack, Hyewon Youm, Kake Zhao, Deborah L Zink, Hratch Zokian, George H Addona, Karen Akinsanya, James R Tata, Yusheng Xiong, Jason E Imbriglio,

Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for ... Read more >>

Cell Chem Biol (Cell chemical biology)
[2020, 27(1):32-40.e3]

Cited: 1 time

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Corrigendum to "Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects" [Bioorg. Med. Chem. Lett. 26 (2016) 5724-5728].

Matthew Lombardo, Kate Bender, Clare London, Michael A Plotkin, Melissa Kirkland, Joel Mane, Michele Pachanski, Wayne Geissler, John Cummings, Bahanu Habulihaz, Taro E Akiyama, Jerry Di Salvo, Maria Madeira, Joanna Pols, Mary Ann Powles, Michael F Finley, Eric Johnson, Thomas Roussel, Victor N Uebele, Alejandro Crespo, Dennis Leung, Candice Alleyne, Dorina Trusca, Ying Lei, Andrew D Howard, Feroze Ujjainwalla, James R Tata, Christopher J Sinz,

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2017, 27(5):1333]

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Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects.

Matthew Lombardo, Kate Bender, Clare London, Michael A Plotkin, Melissa Kirkland, Joel Mane, Michele Pachanski, Wayne Geissler, John Cummings, Bahanu Habulihaz, Taro E Akiyama, Jerry Di Salvo, Maria Madeira, Joanna Pols, Mary Ann Powles, Michael F Finley, Eric Johnson, Thomas Roussel, Victor N Uebele, Alejandro Crespo, Dennis Leung, Candice Alleyne, Dorina Trusca, Ying Lei, Andrew D Howard, Feroze Ujjainwalla, James R Tata, Christopher J Sinz,

The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2016, 26(23):5724-5728]

Cited: 5 times

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Discovery of Spirocyclic Aldosterone Synthase Inhibitors as Potential Treatments for Resistant Hypertension.

Whitney L Petrilli, Scott B Hoyt, Clare London, Daniel McMasters, Andreas Verras, Mary Struthers, Doris Cully, Thomas Wisniewski, Ning Ren, Charlene Bopp, Andrea Sok, Qing Chen, Ying Li, Elaine Tung, Wei Tang, Gino Salituro, Ian Knemeyer, Bindhu Karanam, Joseph Clemas, Gaochao Zhou, Jack Gibson, Carrie Ann Shipley, Douglas J MacNeil, Ruth Duffy, James R Tata, Feroze Ujjainwalla, Amjad Ali, Yusheng Xiong,

Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties. ... Read more >>

(ACS medicinal chemistry letters)
[2017, 8(1):128-132]

Cited: 4 times

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Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists.

Jason M Cox, Hong D Chu, Mariappan V Chelliah, John S Debenham, Keith Eagen, Ping Lan, Matthew Lombardo, Clare London, Michael A Plotkin, Unmesh Shah, Zhongxiang Sun, Henry M Vaccaro, Srikanth Venkatraman, Takao Suzuki, Nengxue Wang, Eric R Ashley, Alejandro Crespo, Maria Madeira, Dennis H Leung, Candice Alleyne, Aimie M Ogawa, Sarah Souza, Brande Thomas-Fowlkes, Jerry Di Salvo, Adam Weinglass, Melissa Kirkland, Michele Pachanski, Mary Ann Powles, Effie Tozzo, Taro E Akiyama, Feroze Ujjainwalla, James R Tata, Christopher J Sinz,

Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, ... Read more >>

(ACS medicinal chemistry letters)
[2017, 8(1):49-54]

Cited: 6 times

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A novel series of indazole-/indole-based glucagon receptor antagonists.

Songnian Lin, Fengqi Zhang, Guoqiang Jiang, Sajjad A Qureshi, Xiaodong Yang, Gary G Chicchi, Laurie Tota, Alka Bansal, Edward Brady, Maria Trujillo, Gino Salituro, Corey Miller, James R Tata, Bei B Zhang, Emma R Parmee,

A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2015, 25(19):4143-4147]

Cited: 2 times

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Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression.

Brett Lauring, Andrew K P Taggart, James R Tata, Richard Dunbar, Luzelena Caro, Kang Cheng, Jayne Chin, Steven L Colletti, Josee Cote, Sauzanne Khalilieh, Jiajun Liu, Wen-Lin Luo, Alexandra A Maclean, Laurence B Peterson, Adam B Polis, Waheeda Sirah, Tsuei-Ju Wu, Xuan Liu, Lan Jin, Kenneth Wu, P Douglas Boatman, Graeme Semple, Dominic P Behan, Daniel T Connolly, Eseng Lai, John A Wagner, Samuel D Wright, Cynthia Cuffie, Yale B Mitchel, Daniel J Rader, John F Paolini, M Gerard Waters, Andrew Plump,

Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D₂, which mediates ... Read more >>

Sci Transl Med (Science translational medicine)
[2012, 4(148):148ra115]

Cited: 45 times

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(1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (MK-1903): a potent GPR109a agonist that lowers free fatty acids in humans.

P Douglas Boatman, Brett Lauring, Thomas O Schrader, Michelle Kasem, Benjamin R Johnson, Philip Skinner, Jae-Kyu Jung, Jerry Xu, Martin C Cherrier, Peter J Webb, Graeme Semple, Carleton R Sage, Jens Knudsen, Ruoping Chen, Wen-Lin Luo, Luzelena Caro, Josee Cote, Eseng Lai, John Wagner, Andrew K Taggart, Ester Carballo-Jane, Milton Hammond, Steven L Colletti, James R Tata, Daniel T Connolly, M Gerard Waters, Jeremy G Richman,

G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2012, 55(8):3644-3666]

Cited: 16 times

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Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes.

Yusheng Xiong, Jian Guo, Mari R Candelore, Rui Liang, Corey Miller, Qing Dallas-Yang, Guoqiang Jiang, Peggy E McCann, Sajjad A Qureshi, Xinchun Tong, Shiyao Sherrie Xu, Jackie Shang, Stella H Vincent, Laurie M Tota, Michael J Wright, Xiaodong Yang, Bei B Zhang, James R Tata, Emma R Parmee,

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2012, 55(13):6137-6148]

Cited: 32 times

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Discovery of aminoheterocycles as potent and brain penetrant prolylcarboxypeptidase inhibitors.

Zhicai Wu, Cangming Yang, Thomas H Graham, Andreas Verras, Renee M Chabin, Suoyu Xu, Xinchun Tong, Dan Xie, Mike E Lassman, Urmi R Bhatt, Margarita M Garcia-Calvo, Zhu Shen, Qing Chen, Kelly Bleasby, Ranabir Sinharoy, Jeffrey J Hale, James R Tata, Shirly Pinto, Steven L Colletti, Dong-Ming Shen,

Efforts were dedicated to develop potent and brain penetrant prolylcarboxypeptidase (PrCP) inhibitors by replacing the amide group of original leads 1 and 2 with heterocycles. Aminopyrimidines including compound 32a were identified to display good PrCP inhibitory activity (32a, IC(50)=43 nM) and impressive ability to penetrate brain in mice (brain/plasma ratio: ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2012, 22(4):1727-1730]

Cited: 4 times

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Discovery of a new class of potent prolylcarboxypeptidase inhibitors derived from alanine.

Zhicai Wu, Cangming Yang, Yusheng Xiong, Zhe Feng, Matthew Lombardo, Andreas Verras, Renee M Chabin, Suoyu Xu, Xinchun Tong, Dan Xie, Mike E Lassman, Urmi R Bhatt, Margarita M Garcia-Calvo, Wayne Geissler, Zhu Shen, Qing Chen, Ranabir Sinharoy, Jeffrey J Hale, James R Tata, Shirly Pinto, Dong-Ming Shen, Steven L Colletti,

Efforts to modify the central proline portion of lead compound 4 lead to the discovery of novel prolylcarboxypeptidase (PrCP) inhibitors. Especially, replacement with alanine afforded compound 19 displaying more potent human and mouse PrCP inhibitory activity than 4 and an overall comparable profile. ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2012, 22(4):1774-1778]

Cited: 6 times

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The discovery of non-benzimidazole and brain-penetrant prolylcarboxypeptidase inhibitors.

Thomas H Graham, Hong C Shen, Wensheng Liu, Yusheng Xiong, Andreas Verras, Kelly Bleasby, Urmi R Bhatt, Renee M Chabin, Dunlu Chen, Qing Chen, Margarita Garcia-Calvo, Wayne M Geissler, Huaibing He, Michael E Lassman, Zhu Shen, Xinchun Tong, Elaine C Tung, Dan Xie, Suoyu Xu, Steven L Colletti, James R Tata, Jeffrey J Hale, Shirly Pinto, Dong-Ming Shen,

Novel prolylcarboxypeptidase (PrCP) inhibitors with nanomolar IC(50) values were prepared by replacing the previously described dichlorobenzimidazole-substituted pyrrolidine amides with a variety of substituted benzylamine amides. In contrast to prior series, the compounds demonstrated minimal inhibition shift in whole serum and minimal recognition by P-glycoprotein (P-gp) efflux transporters. The compounds were ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2012, 22(1):658-665]

Cited: 6 times

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The discovery of high affinity agonists of GPR109a with reduced serum shift and improved ADME properties.

Jason E Imbriglio, Daniel DiRocco, Rena Bodner, Subharekha Raghavan, Weichun Chen, Daria Marley, Craig Esser, Tom G Holt, Michael S Wolff, Andrew K P Taggart, M Gerard Waters, James R Tata, Steven L Colletti,

Amino-anthranilic acid derivatives have been identified as a new class of low serum shifted, high affinity full agonists of the human orphan G-protein-coupled receptor GPR109a with improved ADME properties. ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2011, 21(9):2721-2724]

Cited: 5 times

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Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors.

Hong C Shen, Fa-Xiang Ding, Changyou Zhou, Yusheng Xiong, Andreas Verras, Renee M Chabin, Suoyu Xu, Xinchun Tong, Dan Xie, Michael E Lassman, Urmi R Bhatt, Margarita M Garcia-Calvo, Wayne Geissler, Zhu Shen, Dunlu Chen, Ranabir Sinharoy, Jeffery J Hale, James R Tata, Shirly Pinto, Dong-Ming Shen, Steven L Colletti,

A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)'s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2011, 21(5):1299-1305]

Cited: 8 times

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Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core.

Dong-Ming Shen, Edward J Brady, Mari R Candelore, Qing Dallas-Yang, Victor D-H Ding, William P Feeney, Guoquiang Jiang, Margaret E McCann, Steve Mock, Sajjad A Qureshi, Richard Saperstein, Xiaolan Shen, Xinchun Tong, Laurie M Tota, Michael J Wright, Xiaodong Yang, Song Zheng, Kevin T Chapman, Bei B Zhang, James R Tata, Emma R Parmee,

A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2011, 21(1):76-81]

Cited: 9 times

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Discovery of pyrazolyl propionyl cyclohexenamide derivatives as full agonists for the high affinity niacin receptor GPR109A.

Fa-Xiang Ding, Hong C Shen, Larrisa C Wilsie, Mihajlo L Krsmanovic, Andrew K Taggart, Ning Ren, Tian-Quan Cai, Junying Wang, Xinchun Tong, Tom G Holt, Qing Chen, M Gerard Waters, Milton L Hammond, James R Tata, Steven L Colletti,

A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure-activity relationship (SAR) studies were aimed to improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, reduce serum shift and improve pharmacokinetic (PK) profiles. ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2010, 20(11):3372-3375]

Cited: 5 times

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GPR109a agonists. Part 2: pyrazole-acids as agonists of the human orphan G-protein coupled receptor GPR109a.

Jason E Imbriglio, Sookhee Chang, Rui Liang, Subharekha Raghavan, Darby Schmidt, Abby Smenton, Scott Tria, Thomas O Schrader, Jae-Kyu Jung, Craig Esser, Tom G Holt, Michael S Wolff, Andrew K P Taggart, Kang Cheng, Ester Carballo-Jane, M Gerard Waters, James R Tata, Steven L Colletti,

5-Alkyl and aryl-pyrazole-acids have been identified as a new class of selective, small-molecule, agonists of the human orphan G-protein-coupled receptor GPR109a, a high affinity receptor for the HDL-raising drug nicotinic acid. ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2010, 20(15):4472-4474]

Cited: 4 times

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Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate.

Hong C Shen, Fa-Xiang Ding, Subharekha Raghavan, Qiaolin Deng, Silvi Luell, Michael J Forrest, Ester Carballo-Jane, Larissa C Wilsie, Mihajlo L Krsmanovic, Andrew K Taggart, Kenneth K Wu, Tsuei-Ju Wu, Kang Cheng, Ning Ren, Tian-Quan Cai, Qing Chen, Junying Wang, Michael S Wolff, Xinchun Tong, Tom G Holt, M Gerard Waters, Milton L Hammond, James R Tata, Steven L Colletti,

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs. ... Read more >>

J Med Chem (Journal of medicinal chemistry)
[2010, 53(6):2666-2670]

Cited: 16 times

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A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors.

Hong C Shen, Fa-Xiang Ding, Qiaolin Deng, Suoyu Xu, Xinchun Tong, Xiaoping Zhang, Yuli Chen, Gaochao Zhou, Lee-Yuh Pai, Magdalena Alonso-Galicia, Sophie Roy, Bei Zhang, James R Tata, Joel P Berger, Steven L Colletti,

Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationship (SAR) study was focused on improving the sEH inhibitory activity. Aminobenzisoxazoles emerged to be ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2009, 19(19):5716-5721]

Cited: 12 times

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Discovery of 3,3-disubstituted piperidine-derived trisubstituted ureas as highly potent soluble epoxide hydrolase inhibitors.

Hong C Shen, Fa-Xiang Ding, Qiaolin Deng, Suoyu Xu, Hsuan-Shen Chen, Xinchun Tong, Vincent Tong, Xiaoping Zhang, Yuli Chen, Gaochao Zhou, Lee-Yuh Pai, Magdalena Alonso-Galicia, Bei Zhang, Sophie Roy, James R Tata, Joel P Berger, Steven L Colletti,

3,3-Disubstituted piperidine-derived trisubstituted urea entA-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound entA-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2009, 19(18):5314-5320]

Cited: 16 times

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Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement.

Hong C Shen, Fa-Xiang Ding, Siyi Wang, Qiaolin Deng, Xiaoping Zhang, Yuli Chen, Gaochao Zhou, Suoyu Xu, Hsuan-Shen Chen, Xinchun Tong, Vincent Tong, Kaushik Mitra, Sanjeev Kumar, Christine Tsai, Andra S Stevenson, Lee-Yuh Pai, Magdalena Alonso-Galicia, Xiaoli Chen, Stephen M Soisson, Sophie Roy, Bei Zhang, James R Tata, Joel P Berger, Steven L Colletti,

4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target ... Read more >>

J Med Chem (Journal of medicinal chemistry)
[2009, 52(16):5009-5012]

Cited: 19 times

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Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors.

Hong C Shen, Fa-Xiang Ding, Siyi Wang, Suoyu Xu, Hsuan-shen Chen, Xinchun Tong, Vincent Tong, Kaushik Mitra, Sanjeev Kumar, Xiaoping Zhang, Yuli Chen, Gaochao Zhou, Lee-Yuh Pai, Magdalena Alonso-Galicia, Xiaoli Chen, Bei Zhang, James R Tata, Joel P Berger, Steven L Colletti,

Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2009, 19(13):3398-3404]

Cited: 22 times

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Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats.

Hong C Shen, Fa-Xiang Ding, Qiaolin Deng, Larissa C Wilsie, Mihajlo L Krsmanovic, Andrew K Taggart, Ester Carballo-Jane, Ning Ren, Tian-Quan Cai, Tsuei-Ju Wu, Kenneth K Wu, Kang Cheng, Qing Chen, Michael S Wolff, Xinchun Tong, Tom G Holt, M Gerard Waters, Milton L Hammond, James R Tata, Steven L Colletti,

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2009, 52(8):2587-2602]

Cited: 13 times

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