Publications by authors named "Deborah H Slee"

15 Publications

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Evaluation of KP-1199: a novel acetaminophen analog for hemostatic function and antinociceptive effects.

Transfusion 2021 07;61 Suppl 1:S234-S242

United States Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, USA.

Background: Acetaminophen (APAP) is a widely self-prescribed analgesic for mild to moderate pain, but overdose or repeat doses can lead to liver injury and death. Kalyra Pharmaceuticals has developed a novel APAP analog, KP-1199, currently in Phase 1 clinical studies, which lacks hepatotoxicity. In this study, the authors evaluated the antinociceptive effect of KP-1199 on thermal injury-induced nociceptive behaviors as well as hemostatic parameters using human blood samples.

Methods: Full-thickness thermal injury was induced in anesthetized adult male Sprague-Dawley rats. On day 7 post-injury, KP-1199 (30 and 60 mg/kg) or APAP (60 mg/kg) was administered orally. Antinociception of KP-1199 and APAP were assessed at multiple time points using Hargreaves' test. In separate experiments, human whole blood was collected and treated with either KP-1199, APAP, or Vehicle (citrate buffer) at 1× (214 μg/ml) and 10× (2140 μg/ml) concentrations. The treated blood samples were assessed for: clotting function, thrombin generation, and platelet activation.

Results: APAP did not produce antinociceptive activity. KP-1199 treatment significantly increased the nociceptive threshold, and the antinociceptive activity persisted up to 3 h post-treatment. In human samples, 10× APAP caused significantly prolonged clotting times and increased platelet activation, whereas KP-1199 had caused no negative effects on either parameter tested.

Conclusion: These results suggest that KP-1199 possesses antinociceptive activity in a rat model of thermal injury. Since KP-1199 does not induce platelet activation or inhibit coagulation, it presents an attractive alternative to APAP for analgesia, especially for battlefield or surgical scenarios where blood loss and blood clotting are of concern.
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http://dx.doi.org/10.1111/trf.16497DOI Listing
July 2021

Topical delivery of Cyclosporine A into the skin using SPACE-peptide.

J Control Release 2015 Feb 4;199:190-7. Epub 2014 Dec 4.

Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, CA 93106, United States; Convoy Therapeutics, 405 W Cool Drive, Suite 107, Oro Valley, AZ 85704, United States. Electronic address:

Cyclosporine A (CsA) is used for the treatment of psoriasis; however systemic administration of CsA is potentially life threatening and there are long-term side effects. Topical application of CsA has the potential to overcome this hurdle; however, its use is limited by poor water solubility and low permeability. Here, we report the use of a physical mixture of SPACE-peptide and CsA in an aqueous ethanol solution to enhance the dermal absorption of the drug. The aqueous ethanol solution (hydroethanolic solution) containing 5mg/mL CsA and 50mg/mL of free SPACE-peptide (SP50) delivered about 30% of topically applied CsA into the porcine skin in vitro and led to an approximately 9-fold (p<0.01) increase in accumulation in viable epidermis compared to the hydroethanolic solution without SPACE-peptide (control group). In vivo biodistribution and pharmacokinetic studies performed using SKH1 hairless mice also confirmed the efficacy of SP50 in dermal delivery of CsA and also demonstrated its advantages over other routes in terms of minimizing its systemic absorption. Topical application of SP50 significantly increased the localization of CsA in the target skin (113.1±13.6(μg/g)/mg) compared to all other groups (p<0.01). In addition, SP50 led to significantly higher skin/blood ratio (443.4±181.5) and skin/liver ratio (1059.5±110.8) of CsA compared to all other groups (p<0.01). The SP50 formulation reported here offers a promising approach for the dermal delivery of CsA.
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http://dx.doi.org/10.1016/j.jconrel.2014.11.015DOI Listing
February 2015

Topical delivery of siRNA into skin using SPACE-peptide carriers.

J Control Release 2014 Apr 13;179:33-41. Epub 2014 Jan 13.

Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara 93106, USA; Convoy Therapeutics, 405 W Cool Drive, Suite 107, Oro Valley 85704, USA. Electronic address:

Short-interfering RNAs (siRNAs) offer a potential tool for the treatment of skin disorders. However, applications of siRNA for dermatological conditions are limited by their poor permeation across the stratum corneum of the skin and low penetration into the skin's viable cells. In this study, we report the use of SPACE-peptide in combination with a DOTAP-based ethosomal carrier system to enhance skin delivery of siRNA. A DOTAP-based SPACE Ethosomal System significantly enhanced siRNA penetration into porcine skin in vitro by 6.3±1.7-fold (p<0.01) with an approximately 10-fold (p<0.01) increase in epidermis accumulation of siRNA compared to that from an aqueous solution. Penetration of siRNA was also enhanced at the cellular level. Internalization of SPACE-peptide occurred in a concentration dependent manner marked by a shift in intracellular distribution from punctate spots to diffused cytoplasmic staining at a peptide concentration of 10mg/mL. In vitro delivery of GAPDH siRNA by SPACE peptide led to 83.3±3.0% knockdown relative to the control. In vivo experiments performed using female BALB/C mice also confirmed the efficacy of DOTAP-SES in delivering GAPDH-siRNA into skin. Topical application of DOTAP-SES on mice skin resulted in 63.2%±7.7% of GAPDH knockdown, which was significantly higher than that from GAPDH-siRNA PBS (p<0.05). DOTAP-SES formulation reported here may open new opportunities for cutaneous siRNA delivery.
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http://dx.doi.org/10.1016/j.jconrel.2014.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425738PMC
April 2014

Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties.

Bioorg Med Chem Lett 2010 Dec 25;20(24):7259-64. Epub 2010 Oct 25.

Department of Medicinal Chemistry, Neurocrine Biosciences, San Diego, CA 92130, USA.

Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.
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http://dx.doi.org/10.1016/j.bmcl.2010.10.095DOI Listing
December 2010

N-[6-amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A2A receptor antagonists with improved drug like properties and in vivo efficacy.

J Med Chem 2009 Feb;52(3):709-17

Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA.

In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.
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http://dx.doi.org/10.1021/jm800908dDOI Listing
February 2009

2,6-Diaryl-4-acylaminopyrimidines as potent and selective adenosine A(2A) antagonists with improved solubility and metabolic stability.

Bioorg Med Chem Lett 2008 Oct 14;18(20):5402-5. Epub 2008 Sep 14.

Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA.

In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
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http://dx.doi.org/10.1016/j.bmcl.2008.09.048DOI Listing
October 2008

Drugability of extracellular targets: discovery of small molecule drugs targeting allosteric, functional, and subunit-selective sites on GPCRs and ion channels.

Neuropsychopharmacology 2009 Jan 17;34(1):106-25. Epub 2008 Sep 17.

Neurocrine Biosciences Inc., San Diego, CA 92130, USA.

Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and gamma-aminobutyric acid receptors, and the Ca(V)2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.
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http://dx.doi.org/10.1038/npp.2008.149DOI Listing
January 2009

Synthesis of N-pyrimidinyl-2-phenoxyacetamides as adenosine A2A receptor antagonists.

Bioorg Med Chem Lett 2008 Mar 16;18(6):1778-83. Epub 2008 Feb 16.

Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.

A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
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http://dx.doi.org/10.1016/j.bmcl.2008.02.032DOI Listing
March 2008

2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships.

J Med Chem 2008 Mar 29;51(6):1730-9. Epub 2008 Feb 29.

Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.

Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.
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http://dx.doi.org/10.1021/jm701187wDOI Listing
March 2008

2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 1. Structure-activity relationships and optimization of heterocyclic substituents.

J Med Chem 2008 Mar 29;51(6):1719-29. Epub 2008 Feb 29.

Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.

Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.
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http://dx.doi.org/10.1021/jm701185vDOI Listing
March 2008

2,6-Diaryl-4-phenacylaminopyrimidines as potent and selective adenosine A(2A) antagonists with reduced hERG liability.

Bioorg Med Chem Lett 2008 Feb 13;18(4):1269-73. Epub 2008 Jan 13.

Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.

In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.
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http://dx.doi.org/10.1016/j.bmcl.2008.01.036DOI Listing
February 2008

Identification of novel, water-soluble, 2-amino-N-pyrimidin-4-yl acetamides as A2A receptor antagonists with in vivo efficacy.

J Med Chem 2008 Feb 12;51(3):400-6. Epub 2008 Jan 12.

Department of Medicinal Chemistry, Pharmacology and Lead Discovery, Neuroscience, Chemical Development and Preclinical Development, Neurocrine Biosciences, San Diego, CA 92130, USA.

Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.
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http://dx.doi.org/10.1021/jm070623oDOI Listing
February 2008

Selection, synthesis, and structure-activity relationship of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists.

Bioorg Med Chem 2007 Aug 17;15(16):5590-603. Epub 2007 May 17.

Departments of Medicinal Chemistry and Pharmacology, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.

The present article describes a selection of a new class of small molecule antagonists for the h-GnRH receptor, their preparation, and evaluation in vitro. Three computational methods were combined into a consensus score, to rank order virtual templates. The top 5% of templates were further evaluated in silico and assessed for novelty and synthetic accessibility. The tetrahydropyrido[4,3-d]pyrimidine-2,4-dione core was selected for synthesis and evaluated in vitro. Using an array approach for analog design and synthesis, we were able to drive the binding below 10nM for the h-GnRH receptor after two rounds of optimization.
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http://dx.doi.org/10.1016/j.bmc.2007.05.029DOI Listing
August 2007

Inhibition of fructose-1,6-bisphosphatase by a new class of allosteric effectors.

J Biol Chem 2003 Dec 6;278(51):51176-83. Epub 2003 Oct 6.

Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA.

A highly constrained pseudo-tetrapeptide (OC252-324) further defines a new allosteric binding site located near the center of fructose-1,6-bisphosphatase. In a crystal structure, pairs of inhibitory molecules bind to opposite faces of the enzyme tetramer. Each ligand molecule is in contact with three of four subunits of the tetramer, hydrogen bonding with the side chain of Asp187 and the backbone carbonyl of residue 71, and electrostatically interacting with the backbone carbonyl of residue 51. The ligated complex adopts a quaternary structure between the canonical R- and T-states of fructose-1,6-bisphosphatase, and yet a dynamic loop essential for catalysis (residues 52-72) is in a conformation identical to that of the T-state enzyme. Inhibition by the pseudo-tetrapeptide is cooperative (Hill coefficient of 2), synergistic with both AMP and fructose 2,6-bisphosphate, noncompetitive with respect to Mg2+, and uncompetitive with respect to fructose 1,6-bisphosphate. The ligand dramatically lowers the concentration at which substrate inhibition dominates the kinetics of fructose-1,6-bisphosphatase. Elevated substrate concentrations employed in kinetic screens may have facilitated the discovery of this uncompetitive inhibitor. Moreover, the inhibitor could mimic an unknown natural effector of fructose-1,6-bisphosphatase, as it interacts strongly with a conserved residue of undetermined functional significance.
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http://dx.doi.org/10.1074/jbc.M308396200DOI Listing
December 2003

Pyrrolopyrazinedione-based inhibitors of human hormone-sensitive lipase.

J Med Chem 2003 Mar;46(7):1120-2

Ontogen Corporation, 6451 El Camino Real, Carlsbad, California 92009, USA.

The regulation of lipid metabolism and it's effect on glucose control and diabetes has received intense interest. Hormone-sensitive lipase (HSL) is a vital enzyme in lipid metabolism. A series of novel pyrrolopyrazinediones has been discovered that demonstrate submicromolar activity both in the enzyme assay and in a (14)C-emulsion assay employing cholesteryl oleate as a substrate as a secondary measure of HSL activity. These compounds represent novel inhibitors of the human HSL enzyme.
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http://dx.doi.org/10.1021/jm020460yDOI Listing
March 2003
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