Publications by authors named "John M Keith"

27 Publications

  • Page 1 of 1

Heteroarylureas with fused bicyclic diamine cores as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2020 10 9;30(20):127463. Epub 2020 Aug 9.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2020.127463DOI Listing
October 2020

The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors.

Bioorg Med Chem Lett 2016 07 5;26(13):3109-3114. Epub 2016 May 5.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.

The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (Vd) obtained from pharmacokinetic (PK) experiments as very high Vds did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement.
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http://dx.doi.org/10.1016/j.bmcl.2016.05.001DOI Listing
July 2016

A Single Amino Acid Difference between Mouse and Human 5-Lipoxygenase Activating Protein (FLAP) Explains the Speciation and Differential Pharmacology of Novel FLAP Inhibitors.

J Biol Chem 2016 Jun 16;291(24):12724-12731. Epub 2016 Apr 16.

Discovery Sciences, Janssen Research and Development, San Diego, California 92121. Electronic address:

5-Lipoxygenase activating protein (FLAP) plays a critical role in the metabolism of arachidonic acid to leukotriene A4, the precursor to the potent pro-inflammatory mediators leukotriene B4 and leukotriene C4 Studies with small molecule inhibitors of FLAP have led to the discovery of a drug binding pocket on the protein surface, and several pharmaceutical companies have developed compounds and performed clinical trials. Crystallographic studies and mutational analyses have contributed to a general understanding of compound binding modes. During our own efforts, we identified two unique chemical series. One series demonstrated strong inhibition of human FLAP but differential pharmacology across species and was completely inactive in assays with mouse or rat FLAP. The other series was active across rodent FLAP, as well as human and dog FLAP. Comparison of rodent and human FLAP amino acid sequences together with an analysis of a published crystal structure led to the identification of amino acid residue 24 in the floor of the putative binding pocket as a likely candidate for the observed speciation. On that basis, we tested compounds for binding to human G24A and mouse A24G FLAP mutant variants and compared the data to that generated for wild type human and mouse FLAP. These studies confirmed that a single amino acid mutation was sufficient to reverse the speciation observed in wild type FLAP. In addition, a PK/PD method was established in canines to enable preclinical profiling of mouse-inactive compounds.
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http://dx.doi.org/10.1074/jbc.M116.725325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933458PMC
June 2016

Preclinical Characterization of the FAAH Inhibitor JNJ-42165279.

ACS Med Chem Lett 2015 Dec 2;6(12):1204-8. Epub 2015 Nov 2.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.

The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677372PMC
December 2015

Polypharmacology of Small-Molecule Modulators of the 5-Lipoxygenase Activating Protein (FLAP) Observed via a High-throughput Lipidomics Platform.

J Biomol Screen 2016 Feb 6;21(2):127-35. Epub 2015 Oct 6.

Discovery Sciences, Janssen Research & Development, LLC, La Jolla, CA, USA

Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small-molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high-throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds.
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http://dx.doi.org/10.1177/1087057115607815DOI Listing
February 2016

1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2014 Mar 31;24(5):1280-4. Epub 2014 Jan 31.

Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, United States.

A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.
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http://dx.doi.org/10.1016/j.bmcl.2014.01.064DOI Listing
March 2014

Heteroarylureas with spirocyclic diamine cores as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2014 Feb 6;24(3):737-41. Epub 2014 Jan 6.

Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain.
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http://dx.doi.org/10.1016/j.bmcl.2013.12.113DOI Listing
February 2014

One-step conversion of azine N-oxides to α-N-aryltriflamidoazines.

Authors:
John M Keith

J Org Chem 2012 Dec 7;77(24):11313-8. Epub 2012 Dec 7.

Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, California 92121, USA.

Various pyridine, quinoline, isoquinoline, and pyrimidine N-oxides were converted to their corresponding α-N-aryltriflamidoheteroarenes in good yield by treatment with N-aryltriflimides, both neat and in solution, at temperatures ranging from rt to 100 °C.
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http://dx.doi.org/10.1021/jo302014cDOI Listing
December 2012

Heteroaryl urea inhibitors of fatty acid amide hydrolase: structure-mutagenicity relationships for arylamine metabolites.

Bioorg Med Chem Lett 2012 Dec 22;22(24):7357-62. Epub 2012 Oct 22.

Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.

The structure-activity relationships for a series of heteroaryl urea inhibitors of fatty acid amide hydrolase (FAAH) are described. Members of this class of inhibitors have been shown to inactivate FAAH by covalent modification of an active site serine with subsequent release of an aromatic amine from the urea electrophile. Systematic Ames II testing guided the optimization of urea substituents by defining the structure-mutagenicity relationships for the released aromatic amine metabolites. Potent FAAH inhibitors were identified having heteroaryl amine leaving groups that were non-mutagenic in the Ames II assay.
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http://dx.doi.org/10.1016/j.bmcl.2012.10.076DOI Listing
December 2012

Aryl Piperazinyl Ureas as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) in Rat, Dog, and Primate.

ACS Med Chem Lett 2012 Oct 22;3(10):823-7. Epub 2012 Aug 22.

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

A series of aryl piperazinyl ureas that act as covalent inhibitors of fatty acid amide hydrolase (FAAH) is described. A potent and selective (does not inhibit FAAH-2) member of this class, JNJ-40355003, was found to elevate the plasma levels of three fatty acid amides: anandamide, oleoyl ethanolamide, and palmitoyl ethanolamide, in the rat, dog, and cynomolgous monkey. The elevation of the levels of these lipids in the plasma of monkeys suggests that FAAH-2 may not play a significant role in regulating plasma levels of fatty acid ethanolamides in primates.
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http://dx.doi.org/10.1021/ml300186gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025847PMC
October 2012

Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: identification of candidates for clinical development.

Bioorg Med Chem Lett 2010 Jul 16;20(14):4210-4. Epub 2010 May 16.

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

The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
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http://dx.doi.org/10.1016/j.bmcl.2010.05.041DOI Listing
July 2010

One-step conversion of azine N-oxides to alpha-1,2,4-triazolo-, 1,2,3-triazolo, imidazolo-, and pyrazoloheteroarenes.

Authors:
John M Keith

J Org Chem 2010 Apr;75(8):2722-5

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, California, USA.

Pyridine, quinoline, isoquinoline, azaindole, and pyrimidine N-oxides were converted to their alpha-triazole and alpha-diazole derivatives by treatment with the corresponding p-toluenesulfonylazoles and Hunig's base at elevated temperatures.
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http://dx.doi.org/10.1021/jo1001017DOI Listing
April 2010

Biochemical and biological properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase.

Anesth Analg 2009 Jan;108(1):316-29

Pain and Related Disorders, Johnson and Johnson Pharmaceutical Research and Development, LLC, San Diego, California 92121, USA.

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family. It catalyzes the hydrolysis of several endogenous biologically active lipids, including anandamide (arachidonoyl ethanolamide), oleoyl ethanolamide, and palmitoyl ethanolamide. These endogenous FAAH substrates have been shown to be involved in a variety of physiological and pathological processes, including synaptic regulation, regulation of sleep and feeding, locomotor activity, pain and inflammation. Here we describe the biochemical and biological properties of a potent and selective FAAH inhibitor, 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide (JNJ-1661010). The time-dependence of apparent IC(50) values at rat and human recombinant FAAH, dialysis and mass spectrometry data indicate that the acyl piperazinyl fragment of JNJ-1661010 forms a covalent bond with the enzyme. This bond is slowly hydrolyzed, with release of the piperazinyl fragment and recovery of enzyme activity. The lack of inhibition observed in a rat liver esterase assay suggests that JNJ-1661010 is not a general esterase inhibitor. JNJ-1661010 is >100-fold preferentially selective for FAAH-1 when compared to FAAH-2. JNJ-1661010 dose-dependently increases arachidonoyl ethanolamide, oleoyl ethanolamide, and palmitoyl ethanolamide in the rat brain. The compound attenuates tactile allodynia in the rat mild thermal injury model of acute tissue damage and in the rat spinal nerve ligation (Chung) model of neuropathic pain. JNJ-1661010 also diminishes thermal hyperalgesia in the inflammatory rat carrageenan paw model. These data suggest that FAAH inhibitors with modes of action similar to JNJ-1661010 may be useful clinically as broad-spectrum analgesics.
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http://dx.doi.org/10.1213/ane.0b013e31818c7cbdDOI Listing
January 2009

2-Aryloxymethylmorpholine histamine H(3) antagonists.

Bioorg Med Chem Lett 2008 Nov 24;18(21):5796-9. Epub 2008 Sep 24.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., San Diego, CA 92121-1126, USA.

The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.077DOI Listing
November 2008

Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2008 Sep 25;18(17):4838-43. Epub 2008 Jul 25.

Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as mechanism-based substrates, forming a covalent bond with Ser241. SAR and PK properties are presented.
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http://dx.doi.org/10.1016/j.bmcl.2008.07.081DOI Listing
September 2008

Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling.

Bioorg Med Chem 2008 Mar 25;16(6):2968-73. Epub 2007 Dec 25.

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

Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
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http://dx.doi.org/10.1016/j.bmc.2007.12.048DOI Listing
March 2008

One step conversion of heteroaromatic-N-oxides to imidazolo-heteroarenes.

Authors:
John M Keith

J Org Chem 2008 Jan 8;73(1):327-30. Epub 2007 Dec 8.

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

Various pyridine-, quinoline-, isoquinoline-, and pyrimidine-N-oxides were converted to their corresponding alpha-imidazoloheteroarenes in good yield by treatment with sulfuryl diimidazole in nonpolar solvents at elevated temperatures.
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http://dx.doi.org/10.1021/jo702038gDOI Listing
January 2008

Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2008 Jan 13;18(1):39-43. Epub 2007 Nov 13.

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

The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2007.11.016DOI Listing
January 2008

Dual serotonin transporter inhibitor/histamine H3 antagonists: development of rigidified H3 pharmacophores.

Bioorg Med Chem Lett 2007 Oct 15;17(19):5325-9. Epub 2007 Aug 15.

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

A series of tetrahydroisoquinolines acting as dual serotonin transporter inhibitor/histamine H(3) antagonists is described. The introduction of polar aromatic spacers as part of the histamine H(3) pharmacophore was explored. A convergent synthesis of the final products allowing late stage introduction of the aromatic side chain was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.08.017DOI Listing
October 2007

Pyrrolidino-tetrahydroisoquinolines bearing pendant heterocycles as potent dual H3 antagonist and serotonin transporter inhibitors.

Bioorg Med Chem Lett 2007 Aug 16;17(15):4374-7. Epub 2007 Mar 16.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, La Jolla, CA 92121, USA.

A series of novel and potent 6-heteroaryl-pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.03.043DOI Listing
August 2007

Pyrrolidino-tetrahydroisoquinolines as potent dual H3 antagonist and serotonin transporter inhibitors.

Bioorg Med Chem Lett 2007 May 4;17(9):2603-7. Epub 2007 Feb 4.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, La Jolla, CA 92121, USA.

A series of novel and potent pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. A highly regio- and diastereoselective synthesis of the pyrrolidino-tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH(3) was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.01.106DOI Listing
May 2007

Novel naphthyridines are histamine H3 antagonists and serotonin reuptake transporter inhibitors.

Bioorg Med Chem Lett 2007 May 4;17(9):2566-9. Epub 2007 Feb 4.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121-1126, USA.

A series of novel tetrahydronaphthyridine-based histamine H(3) ligands that have serotonin reuptake transporter inhibitor activity is described. The 1,2,3,4-tetrahydro-2,6-naphthyridine scaffold is assembled via the addition of a nitrostyrene to a metalated pyridine followed by reduction and cyclization to form the naphthyridine. In vitro biological data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.02.006DOI Listing
May 2007

One-Step conversion of pyridine N-oxides to tetrazolo[1,5-a]pyridines.

Authors:
John M Keith

J Org Chem 2006 Dec;71(25):9540-3

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, California 92121, USA.

Pyridine N-oxides were converted to tetrazolo[1,5-a]pyridines in good to excellent yield by heating in the presence sulfonyl or phosphoryl azides and pyridine in the absence of solvent. Various sulfonyl and phosphoryl azides were screened for reactivity under a standard set of conditions. Diphenyl phosphorazidate was the most convenient reagent and gave high yields. Reaction optimization, scope, and scalability are discussed.
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http://dx.doi.org/10.1021/jo061819jDOI Listing
December 2006

Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Feb 16;17(4):1047-51. Epub 2006 Nov 16.

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

A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H(3) ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.036DOI Listing
February 2007

Dual serotonin transporter/histamine H3 ligands: Optimization of the H3 pharmacophore.

Bioorg Med Chem Lett 2007 Feb 2;17(3):702-6. Epub 2006 Nov 2.

Johnson & Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.089DOI Listing
February 2007

Exploration of the Mitsunobu reaction with Tosyl- and Boc-hydrazones as nucleophilic agents.

J Org Chem 2006 Sep;71(18):7113-6

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

Tosyl- and Boc-hydrazones were found to be effective nucleophiles in the Mitsunobu reaction. Tosyl hydrazones reacted cleanly with primary and secondary alcohols when co-administered to a cooled DBAD/PPh3 or DEAD/PPh3 complex. Boc-hydrazones required electron-withdrawing substituents to participate in the reaction.
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http://dx.doi.org/10.1021/jo061185gDOI Listing
September 2006

Asymmetric hydrocyanation of hydrazones catalyzed by lanthanide--PYBOX complexes.

Org Lett 2004 Jan;6(2):153-5

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

[reaction: see text] The asymmetric addition of HCN to hydrazones is catalyzed in high yield and good-to-excellent enantioselectivity by the easily prepared (PhPYBOX)ErCl3 complex. This constitutes the first example of asymmetric catalytic hydrocyanation of hydrazones.
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http://dx.doi.org/10.1021/ol035844cDOI Listing
January 2004