Publications by authors named "Michael Hack"

30 Publications

  • Page 1 of 1

Impact of Protein Preparation on Resulting Accuracy of FEP Calculations.

J Chem Inf Model 2020 11 2;60(11):5287-5289. Epub 2020 Aug 2.

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

Relative free energy perturbation (FEP) methods have become increasingly popular within the pharmaceutical industry; however, despite time constraints within drug discovery cycles, caution should be applied in the deployment of such methods as protein preparation and system setup can greatly impact the accuracy of free energy predictions.
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http://dx.doi.org/10.1021/acs.jcim.0c00445DOI Listing
November 2020

An Analysis of Different Components of a High-Throughput Screening Library.

J Chem Inf Model 2018 10 26;58(10):2057-2068. Epub 2018 Sep 26.

Janssen Pharmaceutical Research and Development , 3210 Merryfield Row , La Jolla , California 92121 , United States.

Since many projects at pharmaceutical organizations get their start from a high-throughput screening (HTS) campaign, improving the quality of the HTS deck can improve the likelihood of discovering a high-quality lead molecule that can be progressed to a drug candidate. Over the past decade, Janssen has implemented several strategies for external compound acquisition to augment the screening deck beyond the chemical space and number of molecules synthesized for internal projects. In this report, we analyzed the performance of each of those compound collections in the screening campaigns performed internally within Janssen during the last five years. We classified the screening library into two broad categories: Internal and External. The comparison of the performance of these sets of libraries was done by considering the primary, confirmation, and dose response hit rates. Our analysis revealed that Internal compounds (resulting from numerous medicinal chemistry efforts against diverse protein targets) have higher average confirmation hit rates than External ones; however, actives from both categories show similar probabilities of hitting multiple distinct targets. We also investigated the property landscape of both sets of libraries to identify the key elements which make a difference in these categories of compounds. From this analysis, Janssen aims to understand the descriptor landscape of the compounds with the highest hit rates and to use them for improving its future acquisition strategies as well as to inform our plating strategy.
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http://dx.doi.org/10.1021/acs.jcim.8b00258DOI Listing
October 2018

Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction.

J Med Chem 2017 04 16;60(8):3511-3517. Epub 2017 Mar 16.

Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.

A prevalent observation in high-throughput screening and drug discovery programs is the inhibition of protein function by small-molecule compound aggregation. Here, we present the X-ray structural description of aggregation-based inhibition of a protein-protein interaction involving tumor necrosis factor α (TNFα). An ordered conglomerate of an aggregating small-molecule inhibitor (JNJ525) induces a quaternary structure switch of TNFα that inhibits the protein-protein interaction between TNFα and TNFα receptors. SPD-304 may employ a similar mechanism of inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01836DOI Listing
April 2017

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

The effect of pK(a) on pyrimidine/pyridine-derived histamine H4 ligands.

Bioorg Med Chem Lett 2014 Dec 13;24(23):5489-92. Epub 2014 Oct 13.

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

During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2014.10.013DOI Listing
December 2014

Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H₄ receptor antagonists.

J Med Chem 2014 Mar 21;57(6):2429-39. Epub 2014 Feb 21.

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

This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.
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http://dx.doi.org/10.1021/jm401727mDOI Listing
March 2014

Library enhancement through the wisdom of crowds.

J Chem Inf Model 2011 Dec 14;51(12):3275-86. Epub 2011 Nov 14.

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

We present a novel approach for enhancing the diversity of a chemical library rooted on the theory of the wisdom of crowds. Our approach was motivated by a desire to tap into the collective experience of our global medicinal chemistry community and involved four basic steps: (1) Candidate compounds for acquisition were screened using various structural and property filters in order to eliminate clearly nondrug-like matter. (2) The remaining compounds were clustered together with our in-house collection using a novel fingerprint-based clustering algorithm that emphasizes common substructures and works with millions of molecules. (3) Clusters populated exclusively by external compounds were identified as "diversity holes," and representative members of these clusters were presented to our global medicinal chemistry community, who were asked to specify which ones they liked, disliked, or were indifferent to using a simple point-and-click interface. (4) The resulting votes were used to rank the clusters from most to least desirable, and to prioritize which ones should be targeted for acquisition. Analysis of the voting results reveals interesting voter behaviors and distinct preferences for certain molecular property ranges that are fully consistent with lead-like profiles established through systematic analysis of large historical databases.
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http://dx.doi.org/10.1021/ci200446yDOI Listing
December 2011

Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists.

Eur J Pharmacol 2011 Sep 12;667(1-3):120-8. Epub 2011 Jun 12.

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

Orexin receptor antagonists are being investigated as therapeutic agents for insomnia and addictive disorders. In this study the interactions between the orexin receptors (orexin 1 receptor and orexin 2 receptor), orexin peptides, and small molecule orexin antagonists were explored. To study these phenomena, a variety of mutant orexin receptors was made and tested using receptor binding and functional assays. Domains of the two orexin receptors were exchanged to show the critical ligand binding domains for orexin peptides and representative selective orexin receptor antagonists. Results from domain exchanges between the orexin receptors suggest that transmembrane domain 3 is crucially important for receptor interactions with small molecule antagonists. These data also suggest that the orexin peptides occupy a larger footprint, interacting with transmembrane domain 1, the amino terminus and transmembrane domain 5 as well as transmembrane domain 3. Transmembrane domain 3 has been shown to be an important part of the small molecule binding pocket common to rhodopsin and β2-adrenergic receptors. Additional orexin receptor 2 point mutations were made based on the common arrangement of receptor transmembrane domains shown in the G-protein coupled receptor crystal structure literature and the impact of orexin 2 receptor residue threonine 135 on the ligand selectivity of the 2 orexin receptors. These data support a model of the orexin receptor binding pocket in which transmembrane domains 3 and 5 are prominent contributors to ligand binding and functional activity. The data also illustrate key contact points for ligand interactions in the consensus small molecule pocket of these receptors.
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http://dx.doi.org/10.1016/j.ejphar.2011.05.074DOI Listing
September 2011

Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists.

Bioorg Med Chem Lett 2010 Dec 17;20(23):7137-41. Epub 2010 Sep 17.

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

Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties.
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http://dx.doi.org/10.1016/j.bmcl.2010.09.023DOI Listing
December 2010

Agonist/antagonist modulation in a series of 2-aryl benzimidazole H4 receptor ligands.

Bioorg Med Chem Lett 2010 Jun 11;20(11):3367-71. Epub 2010 Apr 11.

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

The present work details the transformation of a series of human histamine H(4) agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent and selective histamine H(4) agonist; whereas incorporation of the constrained histamine analog, spinacamine, modulated the functional activity to give a partial agonist. In two separate series, we demonstrate that constraining the terminal amino portion modulated the spectrum of functional activity of histamine H(4) ligands.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.017DOI Listing
June 2010

Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase.

Bioorg Med Chem Lett 2009 Dec 13;19(23):6548-51. Epub 2009 Oct 13.

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

A series of indeno[1,2-c]pyrazoles were discovered to be the first known inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase. The synthesis, structure-activity relationship profile, and in-vitro pharmacological characterization of this inaugural series of HRI kinase inhibitors are detailed.
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http://dx.doi.org/10.1016/j.bmcl.2009.10.033DOI Listing
December 2009

Identification and synthesis of 2,7-diamino-thiazolo[5,4-d]pyrimidine derivatives as TRPV1 antagonists.

Bioorg Med Chem Lett 2009 Jan 13;19(1):40-6. Epub 2008 Nov 13.

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

We have identified and synthesized a series of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists. An exploration of the structure-activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several potent TRPV1 antagonists, including 3, 29, 51, and 57. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia with an ED(50)=0.5mg/kg in rats.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.024DOI Listing
January 2009

A systemic combination therapy with granulocyte-colony stimulating factor plus erythropoietin aggravates the healing process of balloon-injured rat carotid arteries.

Cardiovasc Drugs Ther 2008 Oct 5;22(5):351-62. Epub 2008 Jun 5.

Department of Internal Medicine II, Regensburg University Medical Center, 93053, Regensburg, Germany.

Objective: Percutaneous vascular interventions lead inevitably to a destruction of the endothelial lining at the site of injury. There are conflicting data on the therapeutic benefit of hematopoietic growth factors aiming at mobilisation of circulating endothelial cells to accelerate the reendothelialisation process. Aim of our study was to evaluate the impact of a maximised 7 day-combination therapy with G-CSF plus EPO on the healing process following balloon injury of the rat carotid artery.

Methods And Results: Osmotic pumps to systemically deliver G-CSF and EPO at saturating doses during the first seven days post injury were implanted into the peritoneal cavity of splenectomised male Sprague-Dawley rats. Cytokine treatment resulted in significantly elevated numbers of white blood cells, hematocrit levels, circulating hematopoietic stem cells, and-temporarily-circulating endothelial precursors. Functional reendothelialisation as assessed by Evan's blue staining on day 14 post injury was not affected by the cytokine treatment. The neointimal response was analysed on day 7 and 28 post injury, and was significantly higher at the day 7 timepoint (Cytokines: I/M-ratio 1.10+/-0.09 vs. Saline: 0.36+/-0.06). Cytokine treated rats also displayed higher rates of thrombotic occlusion (Cytokines: 25-33% vs. Saline: 0%). Serum levels of PAI-1, TGFbeta1, and PDGF-BB were not elevated in the cytokine treated rats. The proliferative rates both in the injured vessel wall and the surrounding adventitia as assessed by BrdU incorporation were significantly higher in the cytokine treated animals. The number of CD45(pos) hematopoietic cells was significantly higher in the adventitia of the cytokine treated rats. Vasa vasorum were not found to be significantly different. The increased neointimal response was not due to expression of G-CSF- or EPO-receptors on VSMCs within the vessel wall or myofibroblasts in the adventitia.

Conclusion: The systemic administration of G-CSF plus EPO during the first week after balloon-injury impairs the vascular healing process by increasing the neointimal response and the risk for thrombotic occlusion.
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http://dx.doi.org/10.1007/s10557-008-6117-8DOI Listing
October 2008

Discovery of potent cholecystokinin-2 receptor antagonists: elucidation of key pharmacophore elements by X-ray crystallographic and NMR conformational analysis.

Bioorg Med Chem 2008 Apr 5;16(7):3917-25. Epub 2008 Feb 5.

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

A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pK(i)=7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, (1)H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.
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http://dx.doi.org/10.1016/j.bmc.2008.01.059DOI Listing
April 2008

Synthesis and solid-phase purification of anthranilic sulfonamides as CCK-2 ligands.

Bioorg Med Chem Lett 2007 Dec 29;17(24):6905-9. Epub 2007 Sep 29.

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

A novel strategy for the synthesis of cholecystokinin-2 receptor ligands was developed. The route employs a solution-phase synthesis of a series of anthranilic sulfonamides followed by a resin capture purification strategy to produce multi-milligram quantities of compounds for bioassay. The synthesis was used to produce >100 compounds containing various functional groups, highlighting the general applicability of this strategy and to address specific metabolism issues in our CCK-2 program.
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http://dx.doi.org/10.1016/j.bmcl.2007.09.087DOI Listing
December 2007

2-Aryl benzimidazoles featuring alkyl-linked pendant alcohols and amines as inhibitors of checkpoint kinase Chk2.

Bioorg Med Chem Lett 2007 Dec 4;17(23):6467-71. Epub 2007 Oct 4.

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

A series of benzimidazole compounds containing pendant alcohol and amine moieties was found to be active against checkpoint kinase Chk2. These compounds were prepared to examine a potential hydrogen bond interaction with an active site residue and to investigate replacement of a biaryl linker with an aliphatic system in an effort to improve solubility.
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http://dx.doi.org/10.1016/j.bmcl.2007.09.098DOI Listing
December 2007

SAR studies of 1,5-diarylpyrazole-based CCK1 receptor antagonists.

Bioorg Med Chem Lett 2007 Dec 1;17(23):6493-8. Epub 2007 Oct 1.

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

A high throughput screening campaign revealed compound 1 as a potent antagonist of the human CCK(1) receptor. Here, we report the syntheses and SAR studies of 1,5-diarylpyrazole analogs with various structural modifications of the alkane side chain of the molecule. The difference in affinity between the two enantiomers for the CCK(1) receptor and the flexible nature of the linker led to the design of constrained analogs with increased potency.
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http://dx.doi.org/10.1016/j.bmcl.2007.09.093DOI Listing
December 2007

R3(BDelta23 27)R/I5 chimeric peptide, a selective antagonist for GPCR135 and GPCR142 over relaxin receptor LGR7: in vitro and in vivo characterization.

J Biol Chem 2007 Aug 2;282(35):25425-35. Epub 2007 Jul 2.

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

Both relaxin-3 and its receptor (GPCR135) are expressed predominantly in brain regions known to play important roles in processing sensory signals. Recent studies have shown that relaxin-3 is involved in the regulation of stress and feeding behaviors. The mechanisms underlying the involvement of relaxin-3/GPCR135 in the regulation of stress, feeding, and other potential functions remain to be studied. Because relaxin-3 also activates the relaxin receptor (LGR7), which is also expressed in the brain, selective GPCR135 agonists and antagonists are crucial to the study of the physiological functions of relaxin-3 and GPCR135 in vivo. Previously, we reported the creation of a selective GPCR135 agonist (a chimeric relaxin-3/INSL5 peptide designated R3/I5). In this report, we describe the creation of a high affinity antagonist for GPCR135 and GPCR142 over LGR7. This GPCR135 antagonist, R3(BDelta23-27)R/I5, consists of the relaxin-3 B-chain with a replacement of Gly23 to Arg, a truncation at the C terminus (Gly24-Trp27 deleted), and the A-chain of INSL5. In vitro pharmacological studies showed that R3(BDelta23-27)R/I5 binds to human GPCR135 (IC50=0.67 nM) and GPCR142 (IC50=2.29 nM) with high affinity and is a potent functional GPCR135 antagonist (pA2=9.15) but is not a human LGR7 ligand. Furthermore, R3(BDelta23-27)R/I5 had a similar binding profile at the rat GPCR135 receptor (IC50=0.25 nM, pA2=9.6) and lacked affinity for the rat LGR7 receptor. When administered to rats intracerebroventricularly, R3(BDelta23-27)R/I5 blocked food intake induced by the GPCR135 selective agonist R3/I5. Thus, R3(BDelta23-27)R/I5 should prove a useful tool for the further delineation of the functions of the relaxin-3/GPCR135 system.
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http://dx.doi.org/10.1074/jbc.M701416200DOI Listing
August 2007

Tetrahydroindazole inhibitors of bacterial type II topoisomerases. Part 2: SAR development and potency against multidrug-resistant strains.

Bioorg Med Chem Lett 2007 May 6;17(10):2718-22. Epub 2007 Mar 6.

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

We have previously reported a novel class of tetrahydroindazoles that display potency against a variety of Gram-positive and Gram-negative bacteria, potentially via interaction with type II bacterial topoisomerases. Herein are reported SAR investigations of this new series. Several compounds possessing broad-spectrum potency were prepared. Further, these compounds exhibit activity against multidrug-resistant Gram-positive microorganisms equivalent to that against susceptible strains.
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http://dx.doi.org/10.1016/j.bmcl.2007.03.004DOI Listing
May 2007

Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: synthesis and preliminary SAR analysis.

Bioorg Med Chem Lett 2007 May 6;17(10):2723-7. Epub 2007 Mar 6.

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

In an attempt to search for a new class of antibacterial agents, we have discovered a series of pyrazole analogs that possess good antibacterial activity for Gram-positive and Gram-negative organisms via inhibition of type II bacterial topoisomerases. We have investigated the structure-activity relationships of this series, with an emphasis on the length and conformation of the linker. This work led to the identification of tetrahydroindazole analogs, such as compound 1, as the most potent class of compounds.
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http://dx.doi.org/10.1016/j.bmcl.2007.03.003DOI Listing
May 2007

Identification and optimization of anthranilic sulfonamides as novel, selective cholecystokinin-2 receptor antagonists.

J Med Chem 2006 Oct;49(21):6371-90

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

A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.
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http://dx.doi.org/10.1021/jm060590xDOI Listing
October 2006

Identification of 2-arylbenzimidazoles as potent human histamine H4 receptor ligands.

Bioorg Med Chem Lett 2006 Dec 20;16(23):6043-8. Epub 2006 Sep 20.

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

A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.
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http://dx.doi.org/10.1016/j.bmcl.2006.08.117DOI Listing
December 2006

Acute injury directs the migration, proliferation, and differentiation of solid organ stem cells: evidence from the effect of hypoxia-ischemia in the CNS on clonal "reporter" neural stem cells.

Exp Neurol 2006 May 5;199(1):156-78. Epub 2006 Jun 5.

Department of Pediatrics and The Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.

Clonal neural cells with stem-like features integrate appropriately into the developing and degenerating central and peripheral nervous system throughout the neuraxis. In response to hypoxic-ischemic (HI) injury, previously engrafted, integrated, and quiescent clonal neural stem cells (NSCs) transiently re-enter the cell cycle, migrate preferentially to the site of ischemia, and differentiate into neurons and oligodendrocytes, the neural cell types typically lost following HI brain injury. They also replenish the supply of immature uncommitted resident stem/progenitor cells. Although they yield astrocytes, scarring is inhibited. These responses appear to occur most robustly within a 3-7 day "window" following HI during which signals are elaborated that upregulate genetic programs within the NSC that mediate proliferation, migration, survival, and differentiation, most of which appear to be terminated once the "window closes" and the chronic phase ensues, sending the NSCs into a quiescent state. These insights derived from using the stem cell in a novel role--as a "reporter" cell--to both track and probe the activity of endogenous stem cells as well as to "interrogate" and "report" the genes differentially induced by the acutely vs. chronically injured milieu. NSCs may be capable of the replacement of cells, genes, and non-diffusible factors in both a widespread or more circumscribed manner (depending on the therapeutic demands of the clinical situation). They may be uniquely responsive to some types of neurodegenerative conditions. We submit that these various capabilities are simply the normal expression of the basic homeostasis-preserving biologic properties and attributes of a stem cell which, if used rationally and in concert with this biology, may be exploited for therapeutic ends.
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http://dx.doi.org/10.1016/j.expneurol.2006.04.002DOI Listing
May 2006

Pyrazole CCK(1) receptor antagonists. Part 1: Solution-phase library synthesis and determination of Free-Wilson additivity.

Bioorg Med Chem Lett 2006 Jan 19;16(1):72-6. Epub 2005 Oct 19.

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

High throughput screening revealed compound 1 as a potent antagonist of the CCK(1) receptor. Evaluation of the CCK(1) SAR in a series of these diarylpyrazole antagonists was conducted in a matrix synthesis format revealing additive (Free-Wilson) and non-additive SAR. This use of additive QSAR modeling in conjunction with combinatorial libraries represents a unique approach to the evaluation of SAR interactions between the variables of any combinatorial matrix.
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http://dx.doi.org/10.1016/j.bmcl.2005.09.048DOI Listing
January 2006

Pyrazole CCK(1) receptor antagonists. Part 2: SAR studies by solid-phase library synthesis and determination of Free-Wilson additivity.

Bioorg Med Chem Lett 2006 Jan 19;16(1):77-80. Epub 2005 Oct 19.

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

High-throughput screening revealed compound 1 as a potent antagonist of the CCK(1) receptor. Here, we disclose the synthesis of combinatorial libraries by solid-phase synthesis on Kenner 'safety catch' resin. Additive QSAR models were used to determine a lack of consistent additive SAR within the matrix.
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http://dx.doi.org/10.1016/j.bmcl.2005.09.041DOI Listing
January 2006

Neuronal fate determinants of adult olfactory bulb neurogenesis.

Nat Neurosci 2005 Jul;8(7):865-72

GSF-National Research Center for Environment and Health, Institute for Stem Cell Research, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.

Adult neurogenesis in mammals is restricted to two small regions, including the olfactory bulb, where GABAergic and dopaminergic interneurons are newly generated throughout the entire lifespan. However, the mechanisms directing them towards a specific neuronal phenotype are not yet understood. Here, we demonstrate the dual role of the transcription factor Pax6 in generating neuronal progenitors and also in directing them towards a dopaminergic periglomerular phenotype in adult mice. We present further evidence that dopaminergic periglomerular neurons originate in a distinct niche, the rostral migratory stream, and are fewer derived from precursors in the zone lining the ventricle. This regionalization of the adult precursor cells is further supported by the restricted expression of the transcription factor Olig2, which specifies transit-amplifying precursor fate and opposes the neurogenic role of Pax6. Together, these data explain both extrinsic and intrinsic mechanisms controlling neuronal identity in adult neurogenesis.
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http://dx.doi.org/10.1038/nn1479DOI Listing
July 2005

BM88 is an early marker of proliferating precursor cells that will differentiate into the neuronal lineage.

Eur J Neurosci 2004 Nov;20(10):2509-23

Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, 127 Vassilissis Sofias Avenue, Athens 115 21, Greece.

Progression of progenitor cells towards neuronal differentiation is tightly linked with cell cycle control and the switch from proliferative to neuron-generating divisions. We have previously shown that the neuronal protein BM88 drives neuroblastoma cells towards exit from the cell cycle and differentiation into a neuronal phenotype in vitro. Here, we explored the role of BM88 during neuronal birth, cell cycle exit and the initiation of differentiation in vivo. By double- and triple-labelling with the S-phase marker BrdU or the late G2 and M-phase marker cyclin B1, antibodies to BM88 and markers of the neuronal or glial cell lineages, we demonstrate that in the rodent forebrain, BM88 is expressed in multipotential progenitor cells before terminal mitosis and in their neuronal progeny during the neurogenic interval, as well as in the adult. Further, we defined at E16 a cohort of proliferative progenitors that exit S phase in synchrony, and by following their fate for 24 h we show that BM88 is associated with the dynamics of neuron-generating divisions. Expression of BM88 was also evident in cycling cortical radial glial cells, which constitute the main neurogenic population in the cerebral cortex. In agreement, BM88 expression was markedly reduced and restricted to a smaller percentage of cells in the cerebral cortex of the Small eye mutant mice, which lack functional Pax6 and exhibit severe neurogenesis defects. Our data show an interesting correlation between BM88 expression and the progression of progenitor cells towards neuronal differentiation during the neurogenic interval.
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http://dx.doi.org/10.1111/j.1460-9568.2004.03724.xDOI Listing
November 2004

Reelin signaling directly affects radial glia morphology and biochemical maturation.

Development 2003 Oct;130(19):4597-609

Max-Planck-Institute of Neurobiology, Neuronal Specification, Am Klopferspitz 18a, D-82152 Martinsried, Germany.

Radial glial cells are characterized, besides their astroglial properties, by long radial processes extending from the ventricular zone to the pial surface, a crucial feature for the radial migration of neurons. The molecular signals that regulate this characteristic morphology, however, are largely unknown. We show an important role of the secreted molecule reelin for the establishment of radial glia processes. We describe a significant reduction in ventricular zone cells with long radial processes in the absence of reelin in the cortex of reeler mutant mice. These defects were correlated to a decrease in the content of brain lipid-binding protein (Blbp) and were detected exclusively in the cerebral cortex, but not in the basal ganglia of reeler mice. Conversely, reelin addition in vitro increased the Blbp content and process extension of radial glia from the cortex, but not the basal ganglia. Isolation of radial glia by fluorescent-activated cell sorting showed that these effects are due to direct signaling of reelin to radial glial cells. We could further demonstrate that this signaling requires Dab1, as the increase in Blbp upon reelin addition failed to occur in Dab1-/- mice. Taken together, these results unravel a novel role of reelin signaling to radial glial cells that is crucial for the regulation of their Blbp content and characteristic morphology in a region-specific manner.
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http://dx.doi.org/10.1242/dev.00654DOI Listing
October 2003

Neuronal or glial progeny: regional differences in radial glia fate.

Neuron 2003 Mar;37(5):751-64

Max-Planck Institute of Neurobiology, Am Klopferspitz 18A, D-82152 Planegg-Martinsried, Germany.

The precursor function of the ubiquitous glial cell type in the developing central nervous system (CNS), the radial glia, is largely unknown. Using Cre/loxP in vivo fate mapping studies, we found that radial glia generate virtually all cortical projection neurons but not the interneurons originating in the ventral telencephalon. In contrast to the cerebral cortex, few neurons in the basal ganglia originate from radial glia, and in vitro lineage analysis revealed intrinsic differences in the potential of radial glia from the dorsal and ventral telencephalon. This shows that the progeny of radial glia not only differs profoundly between brain regions but also includes the majority of neurons in some parts of the CNS.
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http://dx.doi.org/10.1016/s0896-6273(03)00116-8DOI Listing
March 2003

Glial cells generate neurons: the role of the transcription factor Pax6.

Nat Neurosci 2002 Apr;5(4):308-15

Max-Planck Institute of Neurobiology, Am Klopferspitz 18a, 82152, Planegg-Martinsreid, Munich, Germany.

Radial glial cells, ubiquitous throughout the developing CNS, guide radially migrating neurons and are the precursors of astrocytes. Recent evidence indicates that radial glial cells also generate neurons in the developing cerebral cortex. Here we investigated the role of the transcription factor Pax6 expressed in cortical radial glia. We showed that radial glial cells isolated from the cortex of Pax6 mutant mice have a reduced neurogenic potential, whereas the neurogenic potential of non-radial glial precursors is not affected. Consistent with defects in only one neurogenic lineage, the number of neurons in the Pax6 mutant cortex in vivo is reduced by half. Conversely, retrovirally mediated Pax6 expression instructs neurogenesis even in astrocytes from postnatal cortex in vitro. These results demonstrated an important role of Pax6 as intrinsic fate determinant of the neurogenic potential of glial cells.
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http://dx.doi.org/10.1038/nn828DOI Listing
April 2002