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ABSTRACT: Polo Like Kinase 2 (PLK2) phosphorylates α-synuclein and is considered a putative therapeutic target for Parkinson's Disease. Several lines of evidence indicate that PLK2 is involved with proper centriole duplication and cell cycle regulation, inhibition of which could impact chromosomal integrity during mitosis. The objectives of the series of experiments presented herein were to assess whether specific inhibition of PLK2 is genotoxic and determine if PLK2 could be considered a tractable pharmacological target for Parkinson's disease. Several selective PLK2 inhibitors, ELN582175 and ELN582646, and their inactive enantiomers, ELN582176 and ELN582647, did not significantly increase the number of micronuclei in the in vitro micronucleus assay. ELN582646 was administered to male Sprague Dawley rats in an exploratory 14-day study where flow cytometric analysis of peripheral blood identified a dose-dependent increase in the number of micronucleated reticulocytes. A follow-up investigative study demonstrated that ELN582646 administered to PLK2 deficient and wildtype mice significantly increased the number of peripheral micronucleated reticulocytes in both genotypes, suggesting that ELN582646-induced genotoxicity is not through the inhibition of PLK2. Furthermore, significant reduction of retinal phosphorylated α-synuclein levels was observed at three non-genotoxic doses, additional data to suggest that pharmacological inhibition of PLK2 is not the cause of the observed genotoxicity. These data, in aggregate, indicate that PLK2 inhibition is a tractable CNS pharmacological target that does not cause genotoxicity at doses and exposures that engage the target in the sensory retina.
Toxicology and Applied Pharmacology 03/2013; · 4.45 Impact Factor
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Simeon Bowers,
Anh P Truong,
Michael Ye, Danielle L Aubele,
Jennifer M Sealy,
R Jeffrey Neitz,
Roy K Hom,
Wayman Chan,
Michael S Dappen,
Robert A Galemmo, [......],
Zhao Ren,
Danny Tam,
Lany Ruslim,
Jeanne Baker,
Deepal Pandya,
Linnea Diep,
Kent Fitzgerald,
Dean R Artis,
John P Anderson,
Marcelle Bergeron
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ABSTRACT: Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
Bioorganic & medicinal chemistry letters 02/2013; · 2.65 Impact Factor
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Albert W Garofalo,
Marc Adler, Danielle L Aubele,
Elizabeth F Brigham,
David Chian,
Maurizio Franzini,
Erich Goldbach,
Grace T Kwong,
Ruth Motter,
Gary D Probst,
Kevin P Quinn,
Lany Ruslim,
Hing L Sham,
Danny Tam,
Pearl Tanaka,
Anh P Truong,
Xiaocong M Ye,
Zhao Ren
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ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.
Bioorganic & medicinal chemistry letters 02/2013; · 2.65 Impact Factor
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Maurizio Franzini,
Xiaocong M Ye,
Marc Adler, Danielle L Aubele,
Albert W Garofalo,
Shawn Gauby,
Erich Goldbach,
Gary D Probst,
Kevin P Quinn,
Pam Santiago,
Hing L Sham,
Danny Tam,
Anh Truong,
Zhao Ren
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ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.
Bioorganic & medicinal chemistry letters 02/2013; · 2.65 Impact Factor
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Xiaocong M Ye,
Andrei W Konradi,
Minghua Sun,
Shendong Yuan, Danielle L Aubele,
Michael Dappen,
Darren Dressen,
Albert W Garofalo,
Jacek J Jagodzinski,
Lee Latimer, [......],
Elizabeth Brigham,
Grace T Kwong,
Chris Willtis,
George Tonn,
Erich Goldbach,
Kevin P Quinn,
Hongbin H Zhang,
John-Michael Sauer,
Michael Bova,
Guriqbal S Basi
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ABSTRACT: Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.
Bioorganic & medicinal chemistry letters 12/2012; · 2.65 Impact Factor
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Albert W Garofalo,
Marc Adler, Danielle L Aubele,
Simeon Bowers,
Maurizio Franzini,
Erich Goldbach,
Colin Lorentzen,
R Jeffrey Neitz,
Gary D Probst,
Kevin P Quinn,
Pam Santiago,
Hing L Sham,
Danny Tam,
Anh P Truong,
Xiaocong M Ye,
Zhao Ren
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ABSTRACT: Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.
Bioorganic & medicinal chemistry letters 11/2012; · 2.65 Impact Factor
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Danielle L Aubele,
Anh P Truong,
Darren B Dressen,
Gary D Probst,
Simeon Bowers,
Matthew N Mattson,
Chris M Semko,
Minghua Sun,
Albert W Garofalo,
Andrei W Konradi, [......],
Karina Wong,
Erich Goldbach,
Kevin P Quinn,
John-Michael Sauer,
Elizabeth F Brigham,
William Wallace,
Lan Nguyen,
Michael P Bova,
Susanna S Hemphill,
Guriqbal Basi
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ABSTRACT: The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.
Bioorganic & medicinal chemistry letters 10/2011; 21(19):5791-4. · 2.65 Impact Factor
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Martin L Neitzel, Danielle L Aubele,
Jennifer L Marugg,
Jacek J Jagodzinski,
Andrei W Konradi,
Michael A Pleiss,
Balazs Szoke,
Wes Zmolek,
Erich Goldbach,
Kevin P Quinn,
John-Michael Sauer,
Elizabeth F Brigham,
William Wallace,
Michael P Bova,
Susanna Hemphill,
Guriqbal Basi
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ABSTRACT: Herein we describe the structure-activity relationship (SAR) of amino-caprolactam analogs derived from amino-caprolactam benzene sulfonamide 1, highlighting affects on the potency of γ-secretase inhibition, selectivity for the inhibition of APP versus Notch processing by γ-secretase and selected pharmakokinetic properties. Amino-caprolactams that are efficacious in reducing the cortical Aβ(x-40) levels in FVB mice via a single 100 mpk IP dose are highlighted.
Bioorganic & medicinal chemistry letters 06/2011; 21(12):3715-20. · 2.65 Impact Factor
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Xiaocong M Ye,
Andrei W Konradi,
Jenifer Smith, Danielle L Aubele,
Albert W Garofalo,
Jennifer Marugg,
Marty L Neitzel,
Chris M Semko,
Hing L Sham,
Minghua Sun,
Anh P Truong,
Jing Wu,
Hongbin Zhang,
Erich Goldbach,
John-Michael Sauer,
Elizabeth F Brigham,
Michael Bova,
Guriqbal S Basi
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ABSTRACT: Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
Bioorganic & medicinal chemistry letters 06/2010; 20(12):3502-6. · 2.65 Impact Factor
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Guriqbal S Basi,
Susanna Hemphill,
Elizabeth F Brigham,
Anna Liao, Danielle L Aubele,
Jeanne Baker,
Robin Barbour,
Michael Bova,
Xiao-Hua Chen,
Michael S Dappen, [......],
Jing Wu,
Ying-Zi Xu,
Albert W Garofalo,
John Michael Sauer,
Andrei W Konradi,
Daniel Ness,
George Shopp,
Michael A Pleiss,
Stephen B Freedman,
Dale Schenk
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ABSTRACT: Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy.
In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aβ40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aβ production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aβ was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aβ reduction vs. Notch signaling endpoints in periphery.
The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aβ production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aβ in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aβ was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested.
The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.
Alzheimer's Research and Therapy 01/2010; 2(6):36.
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Anh P Truong, Danielle L Aubele,
Gary D Probst,
Martin L Neitzel,
Chris M Semko,
Simeon Bowers,
Darren Dressen,
Roy K Hom,
Andrei W Konradi,
Hing L Sham, [......],
Kevin P Quinn,
John-Michael Sauer,
Elizabeth F Brigham,
William Wallace,
Lan Nguyen,
Susanna S Hemphill,
Michael P Bova,
Frédérique Bard,
Ted A Yednock,
Guriqbal Basi
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ABSTRACT: In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.
Bioorganic & medicinal chemistry letters 08/2009; 19(17):4920-3. · 2.65 Impact Factor
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Angewandte Chemie International Edition 06/2005; 44(22):3485-8. · 13.45 Impact Factor
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Angewandte Chemie 04/2005; 117(22):3551 - 3554.
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ABSTRACT: Homobenzylic amides and carbamates, upon single-electron oxidation, undergo mesolytic cleavage reactions to form acyliminium ions. Appending nucleophilic groups to these substrates results in cyclization reactions to form N-acylaminals. The N-methylquinolinium ion that serves as the photooxidant in these reactions can function as a catalyst when dioxygen is introduced into these reactions, representing a unique method for effecting catalytic, aerobic oxidations. Herein we present a full account of our studies on catalytic aerobic electron-transfer-initiated cyclization reactions of homobenzylic amides and carbamates, with particular emphasis on the roles of the amide group, the nucleophilic group, and the functionality in the tether in promoting efficient ring constructions and altering reaction mechanisms.
Advanced Synthesis & Catalysis 03/2004; 346(2‐3):359 - 366. · 6.05 Impact Factor
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ABSTRACT: [reaction: see text] In this communication we demonstrate that Prins cyclization reactions occur under very mild conditions when cyclic alpha,beta-unsaturated acetals are employed as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles in water, demonstrating that colloidal suspensions can protect highly electrophilic intermediates from hydrolysis. Reactions are experimentally facile and useful in the preparation of a variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol.
Organic Letters 12/2003; 5(23):4521-3. · 5.86 Impact Factor
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ABSTRACT: Acyliminium ions can be prepared through photoinitiated single-electron oxidation reactions of homobenzylic amides and carbamates. Cyclic acyl aminals are formed when these acyliminium ions are appended to nucleophiles such as hydroxyl, ether, and sulfonamide groups. The scope of these reactions is discussed along with mechanistic issues relating to the energetics, chemoselectivity, and stereoelectronic effects of bond activation. [reaction: see text]
Organic Letters 11/2002; 4(20):3443-6. · 5.86 Impact Factor
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ABSTRACT: [reaction: see text] Single-electron oxidation has been employed to initiate heterogenerative cascade cyclization reactions that form polyether compounds under essentially neutral conditions. The reactions proceed through mesolytic benzylic carbon-carbon bond cleavages of homobenzylic ether-derived radical cations followed by intramolecular epoxonium ion formation, leading to further cyclizations. Both oligotetrahydrofuran and tetrahydropyran structures can be prepared by altering substrate topography.
Organic Letters 08/2002; 4(15):2489-92. · 5.86 Impact Factor
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Anh P. Truong, Danielle L. Aubele,
Gary D. Probst,
Martin L. Neitzel,
Chris M. Semko,
Simeon Bowers,
Darren Dressen,
Roy K. Hom,
Andrei W. Konradi,
Hing L. Sham, [......],
Karina Wong,
Erich Goldbach,
Kevin P. Quinn,
John-Michael Sauer,
Elizabeth F. Brigham,
William Wallace,
Lan Nguyen,
Susanna S. Hemphill,
Michael P. Bova,
Guriqbal Basi
Bioorganic & Medicinal Chemistry Letters. 19(17):4920-4923.
