Publications by authors named "Jason C Rech"

20 Publications

  • Page 1 of 1

Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome.

Sci Transl Med 2020 12;12(572)

The Cancer Metabolism Laboratory, the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.

Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 (). Genetic ( mice) and dietary approaches to limit glycine availability resulted in exacerbated diet-induced hyperlipidemia and steatohepatitis, with suppressed mitochondrial/peroxisomal fatty acid β-oxidation (FAO) and enhanced inflammation as the underlying pathways. We explored glycine-based compounds with dual lipid/glucose-lowering properties as potential therapies for NAFLD and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that improved body composition and lowered circulating glucose, lipids, transaminases, proinflammatory cytokines, and steatohepatitis in mice with established NASH induced by a high-fat, cholesterol, and fructose diet. We applied metagenomics, transcriptomics, and metabolomics to explore the underlying mechanisms. The bacterial genus sensu stricto was markedly increased in mice with NASH and decreased after DT-109 treatment. DT-109 induced hepatic FAO pathways, lowered lipotoxicity, and stimulated de novo glutathione synthesis. In turn, inflammatory infiltration and hepatic fibrosis were attenuated via suppression of NF-κB target genes and TGFβ/SMAD signaling. Unlike its effects on the gut microbiome, DT-109 stimulated FAO and glutathione synthesis independent of NASH. In conclusion, impaired glycine metabolism may play a causative role in NAFLD. Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO and glutathione synthesis, thus warranting clinical evaluation.
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http://dx.doi.org/10.1126/scitranslmed.aaz2841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982985PMC
December 2020

1-Pyrrolo[3,2-]pyridine GluN2B-Selective Negative Allosteric Modulators.

ACS Med Chem Lett 2019 Mar 10;10(3):261-266. Epub 2019 Jan 10.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121-1126, United States.

Herein, we disclose a series of selective GluN2B negative allosteric modulators containing a 1-pyrrolo[3,2-]pyridine core. Lead optimization efforts included increasing brain penetration as well as decreasing cytochrome P450 inhibition and hERG channel binding. The series was also optimized to reduce metabolic turnover in human and rat. Compounds , , , and have good in vitro GluN2B potency and good predicted absorption, but moderate to high projected clearance. They were assessed in vivo to determine their target engagement. All four compounds achieved >75% receptor occupancy after an oral dose of 10 mg/kg in rat. Compound receptor occupancy was measured in a dose-response experiment, and its ED was found to be 2.0 mg/kg.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421534PMC
March 2019

From proteomics to discovery of first-in-class ST2 inhibitors active in vivo.

JCI Insight 2018 07 26;3(14). Epub 2018 Jul 26.

Department of Pediatrics and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Soluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses. Dysregulated overproduction of soluble receptors can be pathological, such as soluble ST2 (sST2), a prognostic biomarker in cardiovascular diseases, ulcerative colitis, and graft-versus-host disease (GVHD). Although intervention using an ST2 antibody improves survival in murine GVHD models, sST2 is a challenging target for drug development because it binds to IL-33 via an extensive interaction interface. Here, we report the discovery of small-molecule ST2 inhibitors through a combination of high-throughput screening and computational analysis. After in vitro and in vivo toxicity assessment, 3 compounds were selected for evaluation in 2 experimental GVHD models. We show that the most effective compound, iST2-1, reduces plasma sST2 levels, alleviates disease symptoms, improves survival, and maintains graft-versus-leukemia activity. Our data suggest that iST2-1 warrants further optimization to develop treatment for inflammatory diseases mediated by sST2.
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http://dx.doi.org/10.1172/jci.insight.99208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124397PMC
July 2018

The discovery and preclinical characterization of 6-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists.

Bioorg Med Chem Lett 2016 10 20;26(19):4781-4784. Epub 2016 Aug 20.

Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.

The synthesis, SAR and preclinical characterization of a series of 6-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists is described herein. The lead compounds are potent inhibitors in Ca(2+) flux and whole blood IL-1β P2X7 release assays at both human and mouse isoforms. Compound 1e showed a robust reduction of IL-1β release in a mouse ex vivo model with a 50mg/kg oral dose. Evaluation of compound 1e in the mouse SNI tactile allodynia, carrageenan-induced paw edema or CIA models resulted in no analgesic or anti-inflammatory effects.
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http://dx.doi.org/10.1016/j.bmcl.2016.08.029DOI Listing
October 2016

The evolution of P2X7 antagonists with a focus on CNS indications.

Bioorg Med Chem Lett 2016 08 30;26(16):3838-45. Epub 2016 Jun 30.

Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.

The P2X7 receptor is an ATP-gated nonselective cation channel that has been linked to a number of inflammatory diseases. Activation of the P2X7 receptor by elevated levels of ATP results in the release of proinflammatory cytokines and elevated levels of these cytokines has been associated with a variety of disease states. A number of research groups in both industry and academia have explored the identification of P2X7R antagonists as therapeutic agents. Much of this early effort focused on the treatment of diseases related to peripheral inflammation and resulted in several clinical candidates, none of which were advanced to market. The emerging role of the P2X7 receptor in neuroinflammation and related diseases has resulted in a shift in medicinal chemistry efforts toward the development of centrally penetrant antagonists. This review will highlight the biology supporting the role of P2X7 in diseases related to neuroinflammation and review the recent medicinal chemistry efforts to identify centrally penetrant antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2016.06.048DOI Listing
August 2016

Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain.

ACS Chem Neurosci 2016 Apr 15;7(4):490-7. Epub 2016 Jan 15.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.

Novel 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound 25 (huP2X7 IC50 = 9 nM; rat P2X7 IC50 = 42 nM) achieved 80% receptor occupancy for 6 h when dosed orally at 10 mg/kg in rats as measured by ex vivo radioligand binding autoradiography. Structure-activity relationships within this series are described, as well as in vitro ADME results. In vivo pharmacokinetic data for key compounds is also included.
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http://dx.doi.org/10.1021/acschemneuro.5b00303DOI Listing
April 2016

Preclinical characterization of substituted 6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one P2X7 receptor antagonists.

Bioorg Med Chem Lett 2016 Jan 17;26(2):257-261. Epub 2015 Dec 17.

Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.

The synthesis, SAR, and preclinical characterization of a series of substituted 6,7-dihydro[1,2,4]triazolo[4,3]pyrazin-8(5H)-one P2X7 receptor antagonists are described. Optimized leads from this series comprise some of the most potent human P2X7R antagonists reported to date (IC50s<1nM). They also exhibit sufficient potency and oral bioavailability in rat to enable extensive in vivo profiling. Although many of the disclosed compounds are peripherally restricted, compound 11d is brain penetrant and upon oral administration demonstrated dose-dependent target engagement in rat hippocampus as determined by ex vivo receptor occupancy with radiotracer 5 (ED50=0.8mg/kg).
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http://dx.doi.org/10.1016/j.bmcl.2015.12.052DOI Listing
January 2016

Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists.

Bioorg Med Chem Lett 2015 Aug 9;25(16):3157-63. Epub 2015 Jun 9.

Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address:

The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50 = 7.7 nM) and 7u (P2X7 IC50 =7 .7 nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
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http://dx.doi.org/10.1016/j.bmcl.2015.06.004DOI Listing
August 2015

P2X7 antagonists as potential therapeutic agents for the treatment of CNS disorders.

Prog Med Chem 2014 ;53:65-100

Janssen Research and Development, LLC, San Diego, CA, USA.

The use of P2X7 antagonists to treat inflammatory disorders has garnered considerable interest in recent years. An increasing number of literature reports support the role of P2X7 in inflammatory pathways of the peripheral and central nervous systems (CNSs). A number of CNS indications such as neuropsychiatric and neurodegenerative disorders and neuropathic pain have been linked to a neuroinflammatory response, and clinical studies have shown that inflammatory biomarkers can be mitigated by modulating P2X7. Recent scientific and patent literature describing novel P2X7 antagonists has indicated their use in CNS disorders. In addition, several reports have disclosed the results of administering P2X7 antagonists in pre-clinical models of CNS disease or investigating brain uptake. This review describes small molecule P2X7 antagonists that have first appeared in the literature since 2009 and have potential therapeutic utility in the CNS, or for which new data have emerged implicating their use in CNS indications.
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http://dx.doi.org/10.1016/B978-0-444-63380-4.00002-0DOI Listing
August 2014

Synthesis and Pharmacological Characterization of Two Novel, Brain Penetrating P2X7 Antagonists.

ACS Med Chem Lett 2013 Apr 12;4(4):419-22. Epub 2013 Mar 12.

Janssen Research and Development, LLC , 3210 Merryfield Row, San Diego, California 92121-1126, United States.

The synthesis and preclinical characterization of two novel, brain penetrating P2X7 compounds will be described. Both compounds are shown to be high potency P2X7 antagonists in human, rat, and mouse cell lines and both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular interest as a probe compound for the preclinical assessment of P2X7 blockade in animal models of neuro-inflammation.
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http://dx.doi.org/10.1021/ml400040vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027403PMC
April 2013

Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs.

J Am Chem Soc 2011 Oct 22;133(41):16668-79. Epub 2011 Sep 22.

Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.

The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.
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http://dx.doi.org/10.1021/ja207331mDOI Listing
October 2011

Characterization of 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729209) as a novel TRPV1 antagonist.

Eur J Pharmacol 2011 Aug 10;663(1-3):40-50. Epub 2011 May 10.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

As an integrator of multiple nociceptive and/or inflammatory stimuli, TRPV1 is an attractive therapeutic target for the treatment of various painful disorders. Several TRPV1 antagonists have been advanced into clinical trials and the initial observations suggest that TRPV1 antagonism may be associated with mild hyperthermia and thermal insensitivity in man. However, no clinical efficacy studies have been described to date, making an assessment of risk:benefit impossible. Furthermore, it is not clear whether these early observations are representative of all TRPV1 antagonists and whether additional clinical studies with novel TRPV1 antagonists are required in order to understand optimal compound characteristics. In the present study we describe 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729309) as a novel, TRPV1 antagonist. JNJ-39729209 displaced tritiated resiniferotoxin binding to TRPV1 and prevented TRPV1 activation by capsaicin, protons and heat. In-vivo, JNJ-39729209 blocked capsaicin-induced hypotension, induced a mild hyperthermia and inhibited capsaicin-induced hypothermia in a dose dependent manner. JNJ-39729209 showed significant efficacy against carrageenan- and CFA-evoked thermal hyperalgesia and exhibited significant anti-tussive activity in a guinea-pig model of capsaicin-induced cough. In pharmacokinetic studies, JNJ-39729209 was found to have low clearance, a moderate volume of distribution, good oral bioavailability and was brain penetrant. On the basis of these findings, JNJ-39729209 represents a structurally novel TRPV1 antagonist with potential for clinical development. The advancement of JNJ-39729209 into human clinical trials could be useful in further understanding the analgesic potential of TRPV1 antagonists.
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http://dx.doi.org/10.1016/j.ejphar.2011.05.001DOI Listing
August 2011

Recent advances in the biology and medicinal chemistry of TRPA1.

Future Med Chem 2010 May;2(5):843-58

Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, CA 92121, USA.

The transient receptor potential cation channel, subfamily A, member 1 (TRPA1) is a nonselective cation channel that is highly expressed in small-diameter sensory neurons, where it functions as a polymodal receptor, responsible for detecting potentially harmful chemicals, mechanical forces and temperatures. TRPA1 is also activated and/or sensitized by multiple endogenous inflammatory mediators. As such, TRPA1 likely mediates the pain and neurogenic inflammation caused by exposure to reactive chemicals. In addition, it is also possible that this channel may mediate some of the symptoms of chronic inflammatory conditions such as asthma. We review recent advances in the biology of TRPA1 and summarize the evidence for TRPA1 as a therapeutic drug target. In addition, we provide an update on TRPA1 medicinal chemistry and the progress in the search for novel TRPA1 antagonists.
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http://dx.doi.org/10.4155/fmc.10.29DOI Listing
May 2010

1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines as TRPV1 antagonists with improved properties.

Bioorg Med Chem Lett 2010 Dec 7;20(23):7142-6. Epub 2010 Sep 7.

Johnson & Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121, USA.

Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 ≥237 μg/mL and SIF=11 μg/mL) was significantly improved over compound 1 (pH 2=5 μg/mL and SIF=0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL=0.7 L/kg/h) compared to compound 1 (CL=3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.
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http://dx.doi.org/10.1016/j.bmcl.2010.09.006DOI Listing
December 2010

Total synthesis of theopederin D.

Angew Chem Int Ed Engl 2008 ;47(38):7317-20

Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.

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http://dx.doi.org/10.1002/anie.200802548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440178PMC
October 2008

Catalytic enantioselective addition of arylboronic acids to N-boc imines generated in situ.

Org Lett 2007 Dec 8;9(25):5155-7. Epub 2007 Nov 8.

Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.

The rhodium-catalyzed addition of arylboronic acids to N-Boc imines generated in situ from stable and easily prepared alpha-carbamoyl sulfones has been developed. High enantioselectivities are observed for additions of arylboronic acids with a variety of steric and electronic properties.
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http://dx.doi.org/10.1021/ol702045wDOI Listing
December 2007

Synthesis of potent bicyclic bisarylimidazole c-Jun N-terminal kinase inhibitors by catalytic C-H bond activation.

J Am Chem Soc 2007 Jan;129(3):490-1

Department of Chemistry, University of California, and Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94729, USA.

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http://dx.doi.org/10.1021/ja0676004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556147PMC
January 2007

Concise and stereoselective synthesis of the N7-C25 fragment of psymberin.

Org Lett 2005 Nov;7(23):5175-8

Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.

[reaction: see text] The N7-C25 fragment of the potent and selective cytotoxic agent psymberin has been prepared through a short (12 linear steps, 15 total steps) and stereoselective sequence. Highlights of this route include a very rapid construction of the pentasubstituted arene, a substrate-controlled diastereoselective fragment coupling using a Mukaiyama aldol reaction, and an efficient entry into a key tetrahydropyranyl cyanide.
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http://dx.doi.org/10.1021/ol0520267DOI Listing
November 2005

Stereochemical assignment of the C1-C6 fragment of psymberin by synthesis and natural product degradation.

Org Lett 2005 Sep;7(19):4117-20

Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.

[reaction: see text] Psymberin is a sponge-derived natural product that shows striking selectivity as a cytotoxic agent. Conformational mobility has precluded stereochemical assignment for the acyl fragment of this molecule (psymberic acid) by NMR. Herein we report stereoselective syntheses of all four stereoisomers of psymberic acid. A comparison of the acid-mediated cyclization products of these compounds to the product of psymberin's acidic methanolysis showed the stereochemical configuration of this fragment to be 4S,5S.
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http://dx.doi.org/10.1021/ol051396sDOI Listing
September 2005

An oxidative entry into the amido trioxadecalin ring system.

Org Lett 2003 May;5(9):1495-8

Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.

The amido trioxadecalin ring system is a key structural component of the architecturally interesting anticancer and immunosuppressive agents of the mycalamide, theopederin, and onnamide families of natural products. We report a new entry into this structure in which a mixed acetal serves as a surrogate for a formaldehyde hemiacetal in an addition to an oxidatively generated acyliminium ion. The stereochemical outcome of this process can be explained by the conformational preferences of the product ring system. [reaction: see text]
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http://dx.doi.org/10.1021/ol034273lDOI Listing
May 2003