Publications by authors named "Hillary M Peltier"

10 Publications

  • Page 1 of 1

Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2.

ACS Omega 2019 Apr 12;4(4):6703-6708. Epub 2019 Apr 12.

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

A combination of structure-based drug design and medicinal chemistry efforts led us from benzimidazole-2-carboxamide with modestly active hypoxia-inducible factor prolyl hydroxylase 2 inhibition to certain benzimidazole-2-pyrazole carboxylic acids that were more potent as well as orally efficacious stimulators of erythropoietin secretion in our in vivo mouse model. To better understand the structure-activity relationship, it was necessary to account for (i) the complexation of the ligand with the active site Fe, (ii) the strain incurred by the ligand upon binding, and (iii) certain key water interactions identified by a crystal structure analysis. With this more complete computational model, we arrived at an overarching paradigm that accounted for the potency differences between benzimidazole-2-carboxamide and benzimidazole-2-pyrazole carboxylic acid enzyme inhibitors. Moreover, the computational paradigm allowed us to anticipate that the bioisostere replacement strategy (amide → pyrazole), which had shown success in the benzimidazole series, was not generally applicable to other series. This illustrates that to fully reconcile the important ligand-active site interactions for certain targets, one often needs to move beyond traditional structure-based drug design (such as crystallographic analysis, docking, etc.) and appeal to a higher level of computational theory.
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http://dx.doi.org/10.1021/acsomega.9b00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547624PMC
April 2019

Emerging technologies for metabolite generation and structural diversification.

Bioorg Med Chem Lett 2013 Oct 11;23(20):5471-83. Epub 2013 Aug 11.

AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA 01605, USA. Electronic address:

Multiple technologies have emerged for structural diversification and efficient production of metabolites of drug molecules. These include expanded use of enzymatic and bioorganic transformations that mimic biological systems, biomimetic catalysis and electrochemical techniques. As this field continues to mature the breadth of transformations is growing beyond simple oxidative processes due in part to parallel development of more efficient catalytic methods for functionalization of unactivated scaffolds. These technologies allow for efficient structural diversification of both aromatic and aliphatic substrates in many cases via single step reactions without the use of protecting groups.
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http://dx.doi.org/10.1016/j.bmcl.2013.08.003DOI Listing
October 2013

Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor.

Mol Pharmacol 2011 Jun 3;79(6):910-20. Epub 2011 Mar 3.

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

The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitor of PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), through structure-based drug design methods. The pharmacology of JNJ-42041935 was investigated in enzyme, cellular, and whole-animal systems and was compared with other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pK(I) = 7.3-7.9), 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition, JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses (50 μg/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammation-induced anemia model in rats. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversing inflammation-induced anemia, whereas erythropoietin had no effect. The results demonstrate that JNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition and demonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia.
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http://dx.doi.org/10.1124/mol.110.070508DOI Listing
June 2011

Benzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues.

ACS Med Chem Lett 2010 Dec 5;1(9):526-9. Epub 2010 Oct 5.

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

HIF prolyl 4-hydroxylases (PHD) are a family of enzymes that mediate key physiological responses to hypoxia by modulating the levels of hypoxia inducible factor 1-α (HIF1α). Certain benzimidazole-2-pyrazole carboxylates were discovered to be PHD2 inhibitors using ligand- and structure-based methods and found to be potent, orally efficacious stimulators of erythropoietin secretion in vivo.
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http://dx.doi.org/10.1021/ml100198yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007848PMC
December 2010

Expedient synthesis of N-methyl tubulysin analogues with high cytotoxicity.

J Org Chem 2008 Jun 15;73(12):4362-9. Epub 2008 May 15.

Department of Chemistry, University of California, Berkeley, CA 94720, USA.

An optimized and highly efficient synthesis of potent, bioactive N-methyl tubulysin analogues 2 and 4 has been achieved with > 40% overall yields. This synthesis represents a significant improvement over previously reported syntheses of these and related tubulysin analogues. The stereoselective synthesis of the unnatural amino acid tubuvaline is accomplished using tert-butanesulfinamide chemistry. N-Alkylation to form N-methyl tubuvaline is performed without protection of the tubuvaline alcohol by implementing a unique N-methylation strategy via formation and reduction of a 1,3-tetrahydrooxazine heterocycle. Acylation of the hindered N-methyl tubuvaline amine utilizes a novel sequence of O-acylation followed by an O- to N-acyl transfer to form the hindered amide bond between N-methyl tubuvaline and isoleucine. This high-yielding synthesis should enable the production of large quantities of material for biological studies.
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http://dx.doi.org/10.1021/jo800384xDOI Listing
June 2008

Design, synthesis, and biological properties of highly potent tubulysin D analogues.

Chemistry 2007 ;13(34):9534-41

Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720-1460, USA.

Ten analogues of tubulysin D were synthesized and assayed against established mammalian cell lines, including cancer cells measuring inhibition of cell growth by an MTT assay. These experiments establish for the first time the essential features for the potent cytotoxicity of tubulysin D. The activities of analogues 2 to 5 demonstrate that numerous modifications may be introduced at the C-terminus of the natural product with only modest loss in activity, while the activities of analogues 6 to 8 suggest that a basic amine must be present at the N-terminus to maintain activity. Most surprisingly, analogue 10 establishes that replacement of the chemically labile O-acyl N,O-acetal with the stable N-methyl group results in almost no loss in activity. In aggregate, these structure-activity relationships enable the design of analogues such as 11 that are smaller and considerably more stable than tubulysin D but that maintain most of its potent cell-growth inhibitory activity.
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http://dx.doi.org/10.1002/chem.200701057DOI Listing
February 2008

One-pot asymmetric synthesis of either diastereomer of tert-butanesulfinyl-protected amines from ketones.

J Org Chem 2007 Jan;72(2):626-9

Department of Chemistry, University of California, Berkeley, California 94720, USA.

A one-pot method for the asymmetric synthesis of tert-butanesulfinyl-protected amines is described. Condensation of aryl alkyl and dialkyl ketones with tert-butanesulfinamide followed by in situ reduction with the appropriate reagent provides either diastereomer of the sulfinamide products in good yields and with diastereomeric ratios of up to 99:1.
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http://dx.doi.org/10.1021/jo0616512DOI Listing
January 2007

The total synthesis of tubulysin D.

J Am Chem Soc 2006 Dec;128(50):16018-9

Department of Chemistry, University of California, Berkeley, California 94720, USA.

The first total synthesis of tubulysin D is reported. The development and application of new tert-butanesulfinamide methods allowed for rapid syntheses of the tubuvaline and tubuphenylalanine fragments. Most significantly, a route was devised and implemented to introduce and carry forward the highly labile N,O-acetal functionality. Tubulysin D is the most active member of the tubulysin family, and the efficient synthetic route described herein will allow for the rapid syntheses of analogues to probe the biological activity of this important class of natural products.
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http://dx.doi.org/10.1021/ja067177zDOI Listing
December 2006

N-sulfinyl metalloenamine conjugate additions: asymmetric synthesis of piperidines.

J Org Chem 2005 Sep;70(18):7342-5

Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, California 94720, USA.

[reaction: see text] The first examples of conjugate additions of N-tert-butanesulfinyl metalloenamines are reported. Highly stereoselective conjugate additions (97:3 to 99:1 dr) were observed between metalloenamines derived from N-sulfinyl ketimines and alpha,beta-unsaturated ketones bearing either alkyl or aryl substituents. The conjugate addition products could rapidly be converted with high diastereoselectivity to 2,4,6-trisubstituted piperidines, which are difficult to access by other methods.
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http://dx.doi.org/10.1021/jo051020sDOI Listing
September 2005

Catalytic enantioselective sulfinyl transfer using cinchona alkaloid catalysts.

Org Lett 2005 Apr;7(9):1733-6

Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, California 94720, USA.

[reaction: see text] Practical reaction conditions for the catalytic enantioselective synthesis of sulfinate esters are reported. Commercially available cinchona alkaloids were found to be superior catalysts for the sulfinyl transfer reaction of tert-butanesulfinyl chloride and a variety of benzyl alcohols. Sulfinyl transfer with 2,4,6-trichlorobenzyl alcohol and 10 mol % of the commercially available, inexpensive catalyst quinidine provided the pure sulfinate ester product in 92% isolated yield and with 90% ee.
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http://dx.doi.org/10.1021/ol050275pDOI Listing
April 2005
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