Publications by authors named "Curt A Dvorak"

20 Publications

  • Page 1 of 1

Discovery and SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as 5-HT inhibitors leading to the identification of a clinical candidate.

Bioorg Med Chem Lett 2021 01 7;31:127669. Epub 2020 Nov 7.

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

We report here the synthesis and characterization of a dual 5-HT / 5-HT receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT and 5-HT receptor ligand having a pK = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT and as an inverse agonist in an in vitro functional assay for 5-HT. In a validated in vivo model for central 5-HT activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~27 ng/ml. In a validated in vivo model for central 5-HT activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT receptor binding sites in the frontal cortex of the rat brain with an ED in good agreement with the ED value for central functional effect mediated by 5-HT receptor (ED = 0.8 mg/kg, p.o., 1 h).
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http://dx.doi.org/10.1016/j.bmcl.2020.127669DOI Listing
January 2021

Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793.

ACS Med Chem Lett 2020 Oct 27;11(10):2002-2009. Epub 2020 Apr 27.

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

The orexin system consists of two neuropeptides (orexin-A and orexin-B) that exert their mode of action on two receptors (orexin-1 and orexin-2). While the role of the orexin-2 receptor is established as an important modulator of sleep wake states, the role of the orexin-1 receptor is believed to play a role in addiction, panic, or anxiety. In this manuscript, we describe the optimization of a nonselective substituted azabicyclo[2.2.1]heptane dual orexin receptor antagonist (DORA) into orally bioavailable, brain penetrating, selective orexin-1 receptor (OX1R) antagonists. This resulted in the discovery of our first candidate for clinical development, JNJ-54717793.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549262PMC
October 2020

A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate.

J Med Chem 2018 01 20;61(1):207-223. Epub 2017 Dec 20.

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

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01279DOI Listing
January 2018

4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate.

J Med Chem 2017 06 25;60(11):4559-4572. Epub 2017 May 25.

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

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00408DOI Listing
June 2017

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

Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor.

ACS Med Chem Lett 2015 Sep 20;6(9):1015-8. Epub 2015 Jul 20.

Janssen Research & Development, LLC , San Diego, California 92121, United States.

A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with an EC50 = 16 nM. The compound was found to cross the blood-brain barrier and have good drug-like properties amenable for oral dosing in rat.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569879PMC
September 2015

Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects.

ACS Med Chem Lett 2012 Aug 11;3(8):637-9. Epub 2012 Jun 11.

Janssen Research & Development, LLC , San Diego, California 92121, United States.

Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity.
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http://dx.doi.org/10.1021/ml3000676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025785PMC
August 2012

The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y₂ receptor.

Bioorg Med Chem Lett 2011 Sep 18;21(18):5552-6. Epub 2011 Jul 18.

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

A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC(50)) at the human Neuropeptide Y Y(2) receptor (NPY Y(2)). Six of the 23 analogs tested possessed an NPY Y(2) IC(50) ≤ 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.
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http://dx.doi.org/10.1016/j.bmcl.2011.06.136DOI Listing
September 2011

Novel tetrahydropyrido[3,2-c]pyrroles as 5-HT(7) antagonists.

Bioorg Med Chem Lett 2011 Jan 24;21(1):42-4. Epub 2010 Nov 24.

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

The synthesis and SAR for a novel series of tetrahydropyrido[3,2-c]pyrroles is described. Optimization of the pendant aryl ring lead to high binding affinity at the 5-HT(7) receptor when small lipophilic groups were placed in the para position. Modification of the N-benzyl group and secondary amine were not well tolerated. A representative set of compounds was shown to be functional antagonists of the 5-HT(7) receptor.
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http://dx.doi.org/10.1016/j.bmcl.2010.11.078DOI Listing
January 2011

Diamine-based human histamine H3 receptor antagonists: (4-aminobutyn-1-yl)benzylamines.

Eur J Med Chem 2009 Oct 13;44(10):4098-106. Epub 2009 May 13.

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

A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R(3)R(4)N-); (2) the benzylamine moiety (R(1)R(2)N-); and (3) the point of attachment of the benzylamine group (R(1)R(2)N- in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H(3) antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H(3) binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.
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http://dx.doi.org/10.1016/j.ejmech.2009.04.049DOI Listing
October 2009

Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat.

J Pharmacol Exp Ther 2009 Jul 10;330(1):142-51. Epub 2009 Apr 10.

Neuroscience, Johnson & Johnson PRD, 3210 Merryfield Row, San Diego, CA 92121, USA.

Orexins are peptides produced by lateral hypothalamic neurons that exert a prominent role in the maintenance of wakefulness by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptor located in wake-active structures. Pharmacological blockade of both receptors by the dual OX1/2R antagonist (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide (almorexant) has been shown to promote sleep in animals and humans during their active period. However, the selective distribution of OX1R and OX2R in distinct neuronal circuits may result in a differential impact of these receptors in sleep-wake modulation. The respective role of OX1R and OX2R on sleep in correlation with monoamine release was evaluated in rats treated with selective antagonists alone or in combination. When administered in either phase of the light/dark cycle, the OX2R antagonist 1-(2,4-dibromophenyl)-3-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea (JNJ-10397049) decreased the latency for persistent sleep and increased nonrapid eye movement and rapid eye movement sleep time. Almorexant produced less hypnotic activity, whereas the OX1R antagonist 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea (SB-408124) had no effect. Microdialysis studies showed that either OX2R or OX1/2R antagonism decreased extracellular histamine concentration in the lateral hypothalamus, whereas both OX1R and OX1/2R antagonists increased dopamine release in the prefrontal cortex. Finally, coadministration of the OX1R with the OX2R antagonist greatly attenuated the sleep-promoting effects of the OX2R antagonist. These results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system. In addition, it is suggested that simultaneous inhibition of OX1R attenuates the sleep-promoting effects mediated by selective OX2R blockade, possibly correlated with dopaminergic neurotransmission.
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http://dx.doi.org/10.1124/jpet.109.152009DOI Listing
July 2009

Novel imidazole-based histamine H3 antagonists.

Bioorg Med Chem Lett 2009 Feb 6;19(3):903-7. Epub 2008 Dec 6.

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

A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.114DOI Listing
February 2009

2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT2A antagonists.

Bioorg Med Chem Lett 2008 Mar 30;18(6):2103-8. Epub 2008 Jan 30.

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

The synthesis and SAR for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines is described. Representative compounds were shown to be subtype selective 5-HT(2A) antagonists. Optimal placement of a basic nitrogen relative to the pyrimidine and the presence of a 4-fluorophenyl group in the pyrimidine 4-position was found to have a profound effect on affinity and selectivity.
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http://dx.doi.org/10.1016/j.bmcl.2008.01.090DOI Listing
March 2008

Recent medicinal chemistry of the histamine H3 receptor.

Prog Med Chem 2006 ;44:181-206

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

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http://dx.doi.org/10.1016/S0079-6468(05)44405-7DOI Listing
November 2007

Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists.

J Med Chem 2005 Dec;48(26):8289-98

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

Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
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http://dx.doi.org/10.1021/jm0502081DOI Listing
December 2005

Palladium-catalyzed coupling of pyrazole triflates with arylboronic acids.

J Org Chem 2005 May;70(10):4188-90

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

[reaction: see text] A general protocol for the palladium-mediated Suzuki coupling reaction of pyrazole triflates and aryl boronic acids has been developed. The use of additional dppf ligand was determined to increase product yields allowing for the use of a broad range of reaction substrates.
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http://dx.doi.org/10.1021/jo0477897DOI Listing
May 2005

4-phenoxypiperidines: potent, conformationally restricted, non-imidazole histamine H3 antagonists.

J Med Chem 2005 Mar;48(6):2229-38

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

Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H(3) receptor and several members of these new series were found to be potent H(3) antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H(3) ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H(3) receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.
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http://dx.doi.org/10.1021/jm049212nDOI Listing
March 2005

Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists.

Bioorg Med Chem Lett 2004 Aug;14(16):4225-9

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

Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX(1)R and OX(2)R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX(2)R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX(2)R with a pK(i) of 8.3, has a pK(b) of 7.9, and is 600-fold selective for the OX(2)R over the OX(1)R.
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http://dx.doi.org/10.1016/j.bmcl.2004.06.032DOI Listing
August 2004

The first potent and selective non-imidazole human histamine H4 receptor antagonists.

J Med Chem 2003 Sep;46(19):3957-60

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

Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.
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http://dx.doi.org/10.1021/jm0341047DOI Listing
September 2003

A new class of diamine-based human histamine H3 receptor antagonists: 4-(aminoalkoxy)benzylamines.

J Med Chem 2003 Aug;46(18):3938-44

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

4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H(3) receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a methine group showed greatly reduced binding affinities. Six members of this series were found to be antagonists in a cell-based model of human histamine H(3) receptor activation. One member of this series, 1-[4-(3-piperidin-1-ylpropoxy)benzyl]piperidine (7b), was found to be a selective and potent human H(3) receptor antagonist.
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http://dx.doi.org/10.1021/jm030185vDOI Listing
August 2003