Publications by authors named "Peter J Connolly"

54 Publications

Discovery of JNJ-63576253, a Next-Generation Androgen Receptor Antagonist Active Against Wild-Type and Clinically Relevant Ligand Binding Domain Mutations in Metastatic Castration-Resistant Prostate Cancer.

Mol Cancer Ther 2021 May 1;20(5):763-774. Epub 2021 Mar 1.

Janssen Research and Development, Raritan, New Jersey.

Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0510DOI Listing
May 2021

Discovery of JNJ-63576253: A Clinical Stage Androgen Receptor Antagonist for F877L Mutant and Wild-Type Castration-Resistant Prostate Cancer (mCRPC).

J Med Chem 2021 01 20;64(2):909-924. Epub 2021 Jan 20.

Janssen Research and Development, Spring House, Pennsylvania 19477, United States.

Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with . Subsequent lead optimization of led to amelioration of this pathway and nomination of (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).
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http://dx.doi.org/10.1021/acs.jmedchem.0c01563DOI Listing
January 2021

AKR1C3 mediates pan-AR antagonist resistance in castration-resistant prostate cancer.

Prostate 2020 10 31;80(14):1223-1232. Epub 2020 Jul 31.

Discovery Oncology, Janssen R&D US, Spring House, Pennsylvania.

Background: Antiandrogens are effective therapies that block androgen receptor (AR) transactivation and signaling in over 50% of castration-resistant prostate cancer (CRPC) patients. However, an estimated 30% of responders will develop resistance to these therapies within 2 years. JNJ-pan-AR is a broad-spectrum AR antagonist that inhibits wild-type AR as well as several mutated versions of AR that have emerged in patients on chronic antiandrogen treatment. In this work, we aimed to identify the potential underlying mechanisms of resistance that may result from chronic JNJ-pan-AR treatment.

Methods: The LNCaP JNJR prostate cancer subline was developed by chronically exposing LNCaP parental cells to JNJ-pan-AR. Transcriptomic and proteomic profiling was performed to identify potential drivers and/or biomarkers of the resistant phenotype.

Results: Several enzymes critical to intratumoral androgen biosynthesis, Aldo-keto reductase family 1 member C3 (AKR1C3), UGT2B15, and UGT2B17 were identified as potential upstream regulators of the JNJ-pan-AR resistant cells. While we confirmed the overexpression of all three enzymes in the resistant cells only AKR1C3 expression played a functional role in driving JNJ-pan-AR resistance. We also discovered that AKR1C3 regulates UGT2B15 and UGT2B17 expression in JNJ-pan-AR resistant cells.

Conclusions: This study supports the rationale to further investigate the benefits of AKR1C3 inhibition in combination with antiandrogens to prevent CRPC disease progression.
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http://dx.doi.org/10.1002/pros.24049DOI Listing
October 2020

The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors.

Bioorg Med Chem Lett 2020 07 7;30(14):127243. Epub 2020 May 7.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.
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http://dx.doi.org/10.1016/j.bmcl.2020.127243DOI Listing
July 2020

The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL).

Bioorg Med Chem Lett 2020 06 18;30(12):127198. Epub 2020 Apr 18.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.

Monoacylglycerol lipase (MAGL) has emerged as an attractive drug target because of its important role in regulating the endocannabinoid 2-arachidonoylglycerol (2-AG) and its hydrolysis product arachidonic acid (AA) in the brain. Herein, we report the discovery of a novel series of diazetidinyl diamide compounds 6 and 10 as potent reversible MAGL inhibitors. In addition to demonstrating potent MAGL inhibitory activity in the enzyme assay, the thiazole substituted diazetidinyl diamides 6d-l and compounds 10 were also effective at increasing 2-AG levels in a brain 2-AG accumulation assay in homogenized rat brain. Furthermore, selected compounds have been shown to achieve good brain penetration after oral administration in an animal study.
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http://dx.doi.org/10.1016/j.bmcl.2020.127198DOI Listing
June 2020

Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.

J Pharmacol Exp Ther 2020 03 9;372(3):339-353. Epub 2019 Dec 9.

Janssen Research & Development, LLC, San Diego, California.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.
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http://dx.doi.org/10.1124/jpet.119.262139DOI Listing
March 2020

Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease.

Bioorg Med Chem Lett 2019 12 17;29(23):126743. Epub 2019 Oct 17.

Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, United States.

We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC: 0.01 µM) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.05 µM) and IL6/10 secretion (IC: 0.10/0.06 µM) in the TMD8 B-cell lymphoma line. Compound 40 also inhibited cleavage of the MALT1 substrate RelB (IC: 0.10 µM). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.
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http://dx.doi.org/10.1016/j.bmcl.2019.126743DOI Listing
December 2019

Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy.

Bioorg Med Chem Lett 2018 07 8;28(12):2159-2164. Epub 2018 May 8.

Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.

We designed and synthesized a new series of fatty acid synthase (FASN) inhibitors with potential utility for the treatment of cancer. Extensive SAR studies led to highly active FASN inhibitors with good cellular activity and oral bioavailability, exemplified by compound 34. Compound 34 is a potent inhibitor of human FASN (IC = 28 nM) that effectively inhibits proliferation of A2780 ovarian cells (IC = 13 nM) in lipid-reduced serum (LRS). This cellular activity can be rescued by addition of palmitate, consistent with an on-target effect. Compound 34 is also active in many other cell types, including PC3M (IC = 25 nM) and LnCaP-Vancouver prostate cells (IC = 66 nM), and is highly bioavailable (F 61%) with good exposure after oral administration. In a pharmacodynamics study in H460 lung xenograft-bearing mice, oral treatment with compound 34 results in elevated tumor levels of malonyl-CoA and decreased tumor levels of palmitate, fully consistent with the desired target engagement.
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http://dx.doi.org/10.1016/j.bmcl.2018.05.014DOI Listing
July 2018

Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.

Bioorg Med Chem Lett 2016 11 10;26(21):5346-5349. Epub 2016 Sep 10.

Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA(†).

A series of potent and receptor-selective cannabinoid-1 (CB1) receptor inverse agonists has been discovered. Peripheral selectivity of the compounds was assessed by a mouse tissue distribution study, in which the concentrations of a test compound in both plasma and brain were measured. A number of peripherally selective compounds have been identified through this process. Compound 2p was further evaluated in a 3-week efficacy study in the diet-induced obesity (DIO) mouse model. Beneficial effects on plasma glucose were observed from the compound-treated mice.
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http://dx.doi.org/10.1016/j.bmcl.2016.09.025DOI Listing
November 2016

From Nanodiscs to Isotropic Bicelles: A Procedure for Solution Nuclear Magnetic Resonance Studies of Detergent-Sensitive Integral Membrane Proteins.

Structure 2016 Oct 15;24(10):1830-1841. Epub 2016 Sep 15.

Institute of Biophysical Chemistry, Goethe University, Max-von-Laue Street 9, 60438 Frankfurt, Germany. Electronic address:

Nanodiscs and isotropic bicelles are promising membrane mimetics in the field of solution nuclear magnetic resonance (NMR) spectroscopy of integral membrane proteins (IMPs). Despite varied challenges to solution NMR studies of IMPs, we attribute the paucity of solution NMR structures in these environments to the inability of diverse IMPs to withstand detergent treatment during standard nanodisc and bicelle preparations. Here, we present a strategy that creates small isotropic bicelles from IMPs co-translationally embedded in large nanodiscs using cell-free expression. Our results demonstrate appreciable gains in NMR spectral quality while preserving lipid-IMP contacts. We validate the approach on the detergent-sensitive LspA, which finally allowed us to perform high-quality triple-resonance NMR experiments for structural studies. Our strategy of producing bicelles from nanodiscs comprehensively avoids detergent during expression and preparation and is suitable for solution NMR spectroscopy of lipid-IMP complexes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064851PMC
http://dx.doi.org/10.1016/j.str.2016.07.017DOI Listing
October 2016

A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety.

Bioorg Med Chem Lett 2015 Feb 17;25(3):602-6. Epub 2014 Dec 17.

Pfizer-Makro Technologies, Bridgewater, NJ, USA.

Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, μ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.
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http://dx.doi.org/10.1016/j.bmcl.2014.12.015DOI Listing
February 2015

Time-shared experiments for efficient assignment of triple-selectively labeled proteins.

J Magn Reson 2014 Nov 30;248:81-95. Epub 2014 Sep 30.

Institute of Biophysical Chemistry & Center for Biomolecular Magnetic Resonance, Goethe University, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany. Electronic address:

Combinatorial triple-selective labeling facilitates the NMR assignment process for proteins that are subject to signal overlap and insufficient signal-to-noise in standard triple-resonance experiments. Aiming at maximum amino-acid type and sequence-specific information, the method represents a trade-off between the number of selectively labeled samples that have to be prepared and the number of spectra to be recorded per sample. In order to address the demand of long measurement times, we here propose pulse sequences in which individual phase-shifted transients are stored separately and recombined later to produce several 2D HN(CX) type spectra that are usually acquired sequentially. Sign encoding by the phases of (13)C 90° pulses allows to either select or discriminate against (13)C' or (13)C(α) spins coupled to (15)N. As a result, (1)H-(15)N correlation maps of the various isotopomeric species present in triple-selectively labeled proteins are deconvoluted which in turn reduces problems due to spectral overlap. The new methods are demonstrated with four different membrane proteins with rotational correlation times ranging from 18 to 52 ns.
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http://dx.doi.org/10.1016/j.jmr.2014.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254601PMC
November 2014

Combinatorial triple-selective labeling as a tool to assist membrane protein backbone resonance assignment.

J Biomol NMR 2012 Mar 18;52(3):197-210. Epub 2012 Jan 18.

Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.

Obtaining NMR assignments for slowly tumbling molecules such as detergent-solubilized membrane proteins is often compromised by low sensitivity as well as spectral overlap. Both problems can be addressed by amino-acid specific isotope labeling in conjunction with (15)N-(1)H correlation experiments. In this work an extended combinatorial selective in vitro labeling scheme is proposed that seeks to reduce the number of samples required for assignment. Including three different species of amino acids in each sample, (15)N, 1-(13)C, and fully (13)C/(15)N labeled, permits identification of more amino acid types and sequential pairs than would be possible with previously published combinatorial methods. The new protocol involves recording of up to five 2D triple-resonance experiments to distinguish the various isotopomeric dipeptide species. The pattern of backbone NH cross peaks in this series of spectra adds a new dimension to the combinatorial grid, which otherwise mostly relies on comparison of [(15)N, (1)H]-HSQC and possibly 2D HN(CO) spectra of samples with different labeled amino acid compositions. Application to two α-helical membrane proteins shows that using no more than three samples information can be accumulated such that backbone assignments can be completed solely based on 3D HNCA/HN(CO)CA experiments. Alternatively, in the case of severe signal overlap in certain regions of the standard suite of triple-resonance spectra acquired on uniformly labeled protein, or missing signals due to a lack of efficiency of 3D experiments, the remaining gaps can be filled.
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http://dx.doi.org/10.1007/s10858-012-9601-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725308PMC
March 2012

4-aminopyrimidine-5-carbaldehyde oximes as potent VEGFR-2 inhibitors. Part II.

Bioorg Med Chem Lett 2011 Mar 21;21(6):1815-8. Epub 2011 Jan 21.

Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ 08869, USA.

A series of 4-aminopyrimidine-5-carbaldehyde oxime was discovered to have potent VEGFR-2 inhibitory activity. Described here are the chemistry for analogue synthesis and SAR study results. The PK properties, kinase profiling, and in vivo efficacy study for compound 4b are also discussed.
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http://dx.doi.org/10.1016/j.bmcl.2011.01.053DOI Listing
March 2011

Refolding and characterization of a soluble ectodomain complex of the calcitonin gene-related peptide receptor.

Biochemistry 2010 Mar;49(9):1862-72

Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139, USA.

The calcitonin gene-related peptide (CGRP) receptor is a heterodimer of two membrane proteins: calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). CLR is a class B G-protein-coupled receptor (GPCR), possessing a characteristic large amino-terminal extracellular domain (ECD) important for ligand recognition and binding. Dimerization of CLR with RAMP1 provides specificity for CGRP versus related agonists. Here we report the expression, purification, and refolding of a soluble form of the CGRP receptor comprising a heterodimer of the CLR and RAMP1 ECDs. The extracellular protein domains corresponding to residues 23-133 of CLR and residues 26-117 of RAMP1 were shown to be sufficient for formation of a stable, monodisperse complex. The binding affinity of the purified ECD complex for the CGRP peptide was significantly lower than that of the native receptor (IC(50) of 12 microM for the purified ECD complex vs 233 pM for membrane-bound CGRP receptor), indicating that other regions of CLR and/or RAMP1 are important for peptide agonist binding. However, high-affinity binding to known potent and specific nonpeptide antagonists of the CGRP receptor, including olcegepant and telcagepant (K(D) < 0.02 muM), as well as N-terminally truncated peptides and peptide analogues (140 nM to 1.62 microM) was observed.
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http://dx.doi.org/10.1021/bi901848mDOI Listing
March 2010

Enhanced SAR maps: expanding the data rendering capabilities of a popular medicinal chemistry tool.

J Chem Inf Model 2009 Oct;49(10):2221-30

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 665 Stockton Drive, Exton, Pennsylvania 19341, USA.

We recently introduced SAR maps, a new interactive method for visualizing structure-activity relationships targeted specifically at medicinal chemists. A SAR map renders an R-group decomposition of a congeneric series as a rectangular matrix of cells, each representing a unique combination of R-groups color-coded by a user-selected property of the corresponding compound. In this paper, we describe an enhanced version that greatly expands the types of visualizations that can be displayed inside the cells. Examples include multidimensional histograms and pie charts that visualize the biological profiles of compounds across an entire panel of assays, forms that display specific fields on user-defined layouts, aligned 3D structure drawings that show the relative orientation of different substituents, dose-response curves, images of crystals or diffraction patterns, and many others. These enhancements, which capitalize on the modular architecture of its host application Third Dimension Explorer (3DX), allow the medicinal chemist to interactively analyze complex scaffolds with multiple substitution sites, correlate substituent structure and biological activity at multiple simultaneous dimensions, identify missing analogs or screening data, and produce information-dense visualizations for presentations and publications. The new tool has an intuitive user interface that makes it appealing to experts and nonexperts alike.
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http://dx.doi.org/10.1021/ci900264nDOI Listing
October 2009

A highly selective, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor has potent activity in vitro and in vivo.

Angiogenesis 2009 21;12(3):287-96. Epub 2009 Jun 21.

Cancer Therapeutics Research, Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ, USA.

Angiogenesis is a complex process that relies on a variety of growth factors and signaling pathways to stimulate endothelial cell responses and establish functional blood vessels. Signaling through the vascular endothelial growth factor (VEGF) receptors is an important mediator of angiogenesis, a hallmark of tumor growth and metastasis. Inhibition of signaling through VEGF has been clinically validated with FDA-approvals of bevacizumab, sorafenib, and suntinib. Our goal was to discover an orally available, selective VEGFR-2 inhibitor. A novel oxime, 1-{4-[6-amino-5-(methoxyimino-methyl)-pyrimidin-4-yloxy]-2-chloro-phenyl}-3-ethyl-urea (JNJ-38158471), was identified as a potent and selective inhibitor of VEGFR-2. While JNJ-38158471 shares some structure features with sorafenib, unlike sorafenib, it lacks Raf kinase activity. JNJ-38158471 inhibits VEGFR-2 (IC50 = 40 nM) and closely related tyrosine kinases, Ret (180 nM) and Kit (500 nM); it has no significant activity (>1 microM) against VEGFR-1 and VEGFR-3. At nanomolar levels, it inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay and inhibits VEGF-dependent endothelial migration. Once-daily oral dosing of JNJ-3815871 to nude mice bearing human A431, HCT116, and A375 tumors resulted in up to 90% tumor growth inhibition. Strikingly, after termination of JNJ-38158471 monotherapy-treatment of A375 xenografts, tumor growth delay was significantly prolonged up to 4 weeks. Anti-tumor efficacy correlated well with the observed dose concentrations (on a mg/kg basis) necessary to inhibit VEGF-induced corneal angiogenesis in C57BL/6J mice. In addition, the compound inhibited spontaneous polyp formation in the APC min-mouse model. These data demonstrate that JNJ-38158471 is a well tolerated, orally available, highly selective VEGFR-2 inhibitor that may have therapeutic benefit in human malignancies.
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http://dx.doi.org/10.1007/s10456-009-9151-7DOI Listing
January 2010

Synthesis and evaluation of 2,7-diamino-thiazolo[4,5-d] pyrimidine analogues as anti-tumor epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

Bioorg Med Chem Lett 2009 Apr 21;19(8):2333-7. Epub 2009 Feb 21.

Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ 08869, USA.

2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.
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http://dx.doi.org/10.1016/j.bmcl.2009.02.067DOI Listing
April 2009

Synthesis, in vitro activities of (2-cyclopropoxyphenyl)piperidine derivatives for alpha 1a and alpha 1d adrenergic receptor inhibitors.

Med Chem 2009 Jan;5(1):15-22

Johnson & Johnson Pharmaceutical Research and Development LLC, Drug Discovery Research, PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA.

An alpha 1a- and alpha 1d-adrenergic receptor (AR) selective antagonist may be a more efficacious treatment for BPH/LUTS patients and may have fewer side effects than the existing pharmaceuticals. A facile synthesis for a series of (2-cyclopropoxyphenyl)piperidine derivatives has been developed, in which aryl vinyl ether formation and subsequent cyclopropyl formation provide efficient access to key intermediate N-Boc-4-(2-cyclopropoxyphenyl)piperidine. The synthesized (2-cyclopropoxyphenyl)piperidine derivatives display high affinity and selectivity for alpha1a-AR and alpha1d-AR compared to alpha1b-AR and D2 receptor, Ki values for alpha1a-AR are 0.91 nM to 79.0 nM and alpha1d-AR are 2.0 nM to 57 nM; Ki values for alpha1b-AR are 107 nM to 839.8 nM and D2 receptor are 66.2 nM to 187.1 nM. The selectivity ratios of Ki(alpha1b)/Ki(alpha1a) are 11 to 155 fold, Ki(alpha1b)/Ki(alpha1d) are 6 to 171 fold, Ki(D2)/Ki(alpha1a) are 2 to 158 fold, and Ki(D2)/Ki(alpha1d) are 1.2 to 89 fold. Compound 17a shows improved stability in human liver microsome test (t1/2 = 18 minutes).
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http://dx.doi.org/10.2174/157340609787049280DOI Listing
January 2009

7-[1H-Indol-2-yl]-2,3-dihydro-isoindol-1-ones as dual Aurora-A/VEGF-R2 kinase inhibitors: design, synthesis, and biological activity.

Bioorg Med Chem Lett 2008 Sep 26;18(18):5130-3. Epub 2008 Jul 26.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C, PO Box 300, 1000 Route 202, Raritan, NJ 08869, USA.

A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2008.07.090DOI Listing
September 2008

A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine having dual EGFR/HER2 kinase activity: design, synthesis, and biological activity.

Bioorg Med Chem Lett 2008 Sep 17;18(17):4896-9. Epub 2008 Jul 17.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., PO Box 300, 1000 Route 202, Raritan, NJ 08869, USA.

A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine was synthesized and found to have potent dual EGFR/HER2 kinase inhibitory activity. The structure-based drug design of this molecule as well as the kinase and cellular inhibition of HER2 kinase dependent cell lines will be discussed.
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http://dx.doi.org/10.1016/j.bmcl.2008.07.057DOI Listing
September 2008

4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors.

Bioorg Med Chem Lett 2008 Aug 10;18(16):4615-9. Epub 2008 Jul 10.

Johnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry, 8 Clarke Drive, Cranbury, NJ 08512, USA.

Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.
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http://dx.doi.org/10.1016/j.bmcl.2008.07.020DOI Listing
August 2008

Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases.

Bioorg Med Chem Lett 2008 Jun 10;18(12):3495-9. Epub 2008 May 10.

Johnson & Johnson Pharmaceutical Research & Development, Medicinal Chemistry, 8 Clarke Drive, Cranbury, NJ 08512, USA.

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.
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http://dx.doi.org/10.1016/j.bmcl.2008.05.024DOI Listing
June 2008

Scalable synthesis of the VEGF-R2 kinase inhibitor JNJ-17029259 using ultrasound-mediated addition of MeLi-CeCl3 to a nitrile.

J Org Chem 2008 Feb 3;73(3):1121-3. Epub 2008 Jan 3.

Johnson and Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, New Jersey 08869, USA.

The preparation of the selective VEGF-R2 kinase inhibitor 10 (JNJ-17029259) is described in which the key precursor, 4-(5-isoxazolyl)benzonitrile, undergoes clean transformation to the corresponding cumylamine derivative with CeCl(3)-MeLi in THF. This high-yielding cerium mediated transformation is robust, reproducible, and readily scalable based on a requirement for the anhydrous CeCl(3) to be milled and subjected to ultrasound treatment prior to addition of methyllithium.
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http://dx.doi.org/10.1021/jo7021372DOI Listing
February 2008

(Phenylpiperazinyl)cyclohexylureas: discovery of alpha1a/1d-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS).

Bioorg Med Chem Lett 2008 Jan 22;18(2):640-4. Epub 2007 Nov 22.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA.

Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated with alpha(1) adrenergic receptor antagonists. Unfortunately, currently marketed alpha(1) blockers produce CV-related side effects that are caused by the subtype non-selective nature of the drugs. To overcome this problem, it was postulated that an alpha(1a/1d) subtype-selective antagonist would bring more benefit for the treatment of BPH/LUTS. As a continuation of our effort to develop selective alpha(1a/1d) ligands, a series of (phenylpiperazinyl)cyclohexylureas was synthesized and evaluated for the ability to bind to three cloned human alpha(1)-adrenergic receptor subtypes. Several trans isomers were shown to have equal affinity for both alpha(1a), and alpha(1d) subtypes, with 14- to 47-fold selectivity versus the alpha(1b) subtype and >15-fold selectivity versus dopamine D(2).
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http://dx.doi.org/10.1016/j.bmcl.2007.11.068DOI Listing
January 2008

Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors.

Mol Pharmacol 2008 Feb 1;73(2):338-48. Epub 2007 Nov 1.

Bristol-Myers Squibb, Oncology Drug Discovery, Princeton, NJ 08543, USA.

JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.
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http://dx.doi.org/10.1124/mol.107.041236DOI Listing
February 2008

SAR maps: a new SAR visualization technique for medicinal chemists.

J Med Chem 2007 Nov 25;50(24):5926-37. Epub 2007 Oct 25.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA.

We present structure-activity relationship (SAR) maps, a new, intuitive method for visualizing SARs targeted specifically at medicinal chemists. The method renders an R-group decomposition of a chemical series as a rectangular matrix of cells, each representing a unique combination of R-groups and thus a unique compound. Color-coding the cells by chemical property or biological activity allows patterns to be easily identified and exploited. SAR maps allow the medicinal chemist to interactively analyze complicated datasets with multiple R-group dimensions, rapidly correlate substituent structure and biological activity, assess additivity of substituent effects, identify missing analogs and screening data, and create compelling graphical representations for presentation and publication. We believe that this method fills a long-standing gap in the medicinal chemist's toolset for understanding and rationalizing SAR.
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http://dx.doi.org/10.1021/jm070845mDOI Listing
November 2007

Aminocyclohexylsulfonamides: discovery of metabolically stable alpha(1a/1d)-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS).

Bioorg Med Chem Lett 2007 Nov 18;17(22):6123-8. Epub 2007 Sep 18.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA.

Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated by alpha(1) adrenergic receptor antagonists, but these drugs also produce side effects that are related to their subtype non-selective nature. To overcome this limitation, it was hypothesized that an alpha(1a/1d) subtype-selective antagonist would be efficacious while keeping side effects to a minimum. To discover alpha(1a/1d)-selective antagonists and improve metabolic stability of our previously reported compounds, we have designed and synthesized a series of (phenylpiperazinyl)- or (phenylpiperidinyl)-cyclohexylsulfonamides. By incorporating the information obtained from metabolism studies, we were able to discover several compounds that are both alpha(1a/1d) adrenoceptor subtype selective and show increased stability toward human liver microsomal metabolism. The selectivity profile of these compounds provides great improvement over the commercial drug tamsulosin, hence may pave the way to the development of new and efficacious therapeutic agents with reduced side effects.
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http://dx.doi.org/10.1016/j.bmcl.2007.09.051DOI Listing
November 2007

Design, synthesis, and evaluation of 3,4-disubstituted pyrazole analogues as anti-tumor CDK inhibitors.

Bioorg Med Chem Lett 2007 Aug 6;17(16):4557-61. Epub 2007 Jun 6.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 1000 Route 202, Raritan, NJ 08869, USA.

Two series of 3,4-disubstituted pyrazole analogues, 3-(benzimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (2) and 3-(imidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (3), were synthesized as novel cyclin-dependent kinase (CDK) inhibitors. Representative compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in various human tumor cells. The design, synthesis, and preliminary biological evaluation of these pyrazole compounds are reported.
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http://dx.doi.org/10.1016/j.bmcl.2007.05.092DOI Listing
August 2007

Synthesis and evaluation of pyrazolo[3,4-b]pyridine CDK1 inhibitors as anti-tumor agents.

Bioorg Med Chem Lett 2007 Aug 16;17(15):4297-302. Epub 2007 May 16.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA.

A series of 3,5-disubstituted pyrazolo[3,4-b]pyridine cyclin-dependent kinase (CDK) inhibitors was synthesized. These compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in cultured human tumor cells. Selected compounds were evaluated in an in vivo tumor xenograft model. The synthesis and biological evaluation of these pyrazolo[3,4-b]pyridines and related compounds are reported.
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http://dx.doi.org/10.1016/j.bmcl.2007.05.029DOI Listing
August 2007