Erich Goldbach

Publications (18)40.76 Total impact

• Article: Pharmacological inhibition of Polo Like Kinase 2 (PLK2) does not cause chromosomal damage or result in the formation of micronuclei.

  Kent Fitzgerald, Marcelle Bergeron, Christopher Willits, Simeon Bowers, Danielle L Aubele, Erich Goldbach, George Tonn, Daniel Ness, Andrew Olaharski
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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
• Article: Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors.

  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
• Article: Triazolopyridazine LRRK2 kinase inhibitors.

  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
• Article: Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors.

  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
• Article: Novel cinnoline-based inhibitors of LRRK2 kinase activity.

  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
• Article: Development of ALZET® osmotic pump compatible solvent compositions to solubilize poorly soluble compounds for preclinical studies.

  Rampurna Gullapalli, Angelina Wong, Elizabeth Brigham, Grace Kwong, Angie Wadsworth, Christopher Willits, Kevin Quinn, Erich Goldbach, Bhushan Samant
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  ABSTRACT: Hydrophilic, non-aqueous solvents are frequently used to solubilize poorly water soluble compounds for use in ALZET® osmotic pumps used during the discovery and preclinical stages. Though these solvents exhibit the potential to solubilize several poorly soluble compounds, the solubilized compounds are prone to crystallization up on contact with aqueous fluids in vitro and in vivo. Crystallization of a compound can potentially cause pain at the release site, erratic blood levels, and uneven or delayed pharmacokinetic profiles. In this study, we discussed the development of ALZET® pump compatible hydrophilic, non-aqueous vehicles that solubilized two poorly soluble model compounds (ELND006 and ELN 481594) and prevented their crystallization from solutions in vitro and in vivo. The selected formulations were filled into the pumps at three concentrations for each model compound and investigated for their compatibility with the pumps and the subcutaneous tissue of mice where the pump was inserted. The results showed that the formulations were stable physically with no crystallization and chemically with no degradation and were compatible with the pump and animal tissue. The plasma concentration of ELND006 decreased with time at each dose. The extent of the time-dependent decrease in ELND006 plasma levels increased as the amount of dose delivered increased. This time and dose dependent decrease in ELND006 plasma concentrations was attributed to the known auto-induction of hepatic enzymes by the compound. In contrast, the plasma concentration of ELN 481594 increased significantly at higher dose, likely due to accumulation of the compound.
  Drug Delivery 06/2012; 19(5):239-46. · 1.46 Impact Factor
• Article: A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs.

  Kevin Quinn, Rampurna Prasad Gullapalli, Elaine Merisko-Liversidge, Erich Goldbach, Angelina Wong, Gary G Liversidge, Wherly Hoffman, John-Michael Sauer, John Bullock, George Tonn
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  ABSTRACT: ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ∼11%) is attributed to poor aqueous solubility. In addition, inhibiting amyloid precursor protein but not Notch cleavage is an important goal for gamma secretase inhibitors; therefore, significant variation in bioavailability resulting from food consumption is a potential liability for this class of compounds. The objective of the present study was to determine if an ELND006 nanocrystalline formulation would offer improved and predictable pharmacokinetics. ELND006 was formulated as a nanosuspension with a mean particle size of less than 200 nm, which was stable in particle size and crystallinity for over 1 year. In addition, ELND006 nanosuspension exhibited rapid dissolution in comparison with reference active pharmaceutical ingredient (API). The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake.
  Journal of Pharmaceutical Sciences 12/2011; 101(4):1462-74. · 3.06 Impact Factor
• Article: Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.

  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
• Article: Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration.

  Simeon Bowers, Anh P Truong, R Jeffrey Neitz, Roy K Hom, Jennifer M Sealy, Gary D Probst, David Quincy, Brian Peterson, Wayman Chan, Robert A Galemmo, [......], George Tonn, Kevin P Quinn, John-Michael Sauer, Sarah Wright, Kyle Powell, Lany Ruslim, Zhao Ren, Frédérique Bard, Ted A Yednock, Irene Griswold-Prenner
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  ABSTRACT: The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.
  Bioorganic & medicinal chemistry letters 09/2011; 21(18):5521-7. · 2.65 Impact Factor
• Article: Amino-caprolactam γ-secretase inhibitors showing potential for the treatment of Alzheimer's disease.

  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
• Article: Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model.

  Anh P Truong, Gergley Tóth, Gary D Probst, Jennifer M Sealy, Simeon Bowers, David W G Wone, Darren Dressen, Roy K Hom, Andrei W Konradi, Hing L Sham, [......], Karina Wong, Wes Zmolek, Erich Goldbach, Bhushan Samant, Linda Chen, Hongbing Zhang, David F Nakamura, Kevin P Quinn, Ted A Yednock, John-Michael Sauer
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  ABSTRACT: In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
  Bioorganic & medicinal chemistry letters 11/2010; 20(21):6231-6. · 2.65 Impact Factor
• Article: Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors (Part II).

  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
• Article: Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors.

  Xiaocong M Ye, Andrei W Konradi, Jenifer Smith, Ying-Zi Xu, Darren Dressen, Albert W Garofalo, Jennifer Marugg, Hing L Sham, Anh P Truong, Jacek Jagodzinski, Michael Pleiss, Hongbin Zhang, Erich Goldbach, John-Michael Sauer, Elizabeth Brigham, Michael Bova, Guriqbal S Basi
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  ABSTRACT: Discovery of a series of pyrazolopiperidine sulfonamide based gamma-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.
  Bioorganic & medicinal chemistry letters 02/2010; 20(7):2195-9. · 2.65 Impact Factor
• Source

  Available from: Guriqbal S Basi

  Article: Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.

  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.
• Article: N-Bridged bicyclic sulfonamides as inhibitors of gamma-secretase.

  Simeon Bowers, Gary D Probst, Anh P Truong, Roy K Hom, Andrei W Konradi, Hing L Sham, Albert W Garofalo, Karina Wong, Erich Goldbach, Kevin P Quinn, John-Michael Sauer, William Wallace, Lan Nguyen, Susanna S Hemphill, Michael P Bova, Guriqbal S Basi
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  ABSTRACT: The structural modification of a series of [3.3.1] bicyclic sulfonamide based gamma-secretase inhibitors is described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the metabolic stability of the compounds resulting in an improved in vivo metabolic profile.
  Bioorganic & medicinal chemistry letters 10/2009; 19(24):6952-6. · 2.65 Impact Factor
• Article: Design, synthesis, and structure-activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline gamma-secretase inhibitors.

  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
• Article: Design, synthesis, and structure–activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline γ-secretase inhibitors

  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.
• Article: Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and Efficacious γ-Secretase Inhibitors

  Xiaocong M. Ye, Andrei W. Konradi, Jenifer Smith, Ying-Zi Xu, Darren Dressen, Albert W. Garofalo, Jennifer Marugg, Hing L. Sham, Anh P. Truong, Jacek Jagodzinski, Michael Pleiss, Hongbin Zhang, Erich Goldbach, John-Michael Sauer, Elizabeth Brigham, Michael Bova, Guriqbal S. Basi
  Bioorganic & Medicinal Chemistry Letters. 20(7):2195-2199.