Publications by authors named "Dale J Kempf"

72 Publications

Pyrrolopyrimidine Bumped Kinase Inhibitors for the Treatment of Cryptosporidiosis.

ACS Infect Dis 2021 Feb 10. Epub 2021 Feb 10.

Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, United States.

Bumped kinase inhibitors (BKIs) that target calcium-dependent protein kinase 1 have been well established as potential drug candidates against cryptosporidiosis. Recently, BKI-1649, with a 7-pyrrolo[2,3-]pyrimidin-4-amine, or "pyrrolopyrimidine", central scaffold, has shown improved efficacy in mouse models of at substantially reduced doses compared to previously explored analogs of the pyrazolopyrimidine scaffold. Here, two pyrrolopyrimidines with varied substituent groups, BKI-1812 and BKI-1814, were explored in several in vitro and in vivo models and show improvements in potency over the previously utilized pyrazolopyrimidine bumped kinase inhibitors while maintaining equivalent results in other key properties, such as toxicity and efficacy, with their pyrazolopyrimidine isosteric counterparts.
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http://dx.doi.org/10.1021/acsinfecdis.0c00803DOI Listing
February 2021

Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Growth.

ACS Omega 2021 Jan 13;6(3):2284-2311. Epub 2021 Jan 13.

AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States.

With the emergence of multi-drug-resistant strains of there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-à-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles () are described, which were identified following phenotypic screening of the Eli Lilly corporate library against . The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead , with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to , and under replicating conditions, demonstrated bactericidal activity against . Unfortunately, compound had no efficacy in an acute model of TB infection; this was most likely due to the exposure remaining above the minimal inhibitory concentration for only a limited time.
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http://dx.doi.org/10.1021/acsomega.0c05589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841955PMC
January 2021

Assembling Pharma Resources to Tackle Diseases of Underserved Populations.

ACS Med Chem Lett 2020 Jun 27;11(6):1094-1100. Epub 2020 Mar 27.

Discovery and Development Sciences, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States.

Tropical diseases that disproportionally affect the world's poorest people have traditionally been neglected from research efforts toward the discovery and development of new and effective therapies. Over the past two decades, major global health funders have made efforts to bring together various research institutions to work together in these disease areas offering little or no commercial return. This work describes the genesis and growth of an informal program devoted to contributing to new therapies for neglected tropical diseases within the environment of a major biopharmaceutical company (AbbVie).
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http://dx.doi.org/10.1021/acsmedchemlett.0c00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294558PMC
June 2020

Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned.

Int J Parasitol 2020 05 26;50(5):413-422. Epub 2020 Mar 26.

Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA. Electronic address:

Bumped Kinase Inhibitors, targeting Calcium-dependent Protein Kinase 1 in apicomplexan parasites with a glycine gatekeeper, are promising new therapeutics for apicomplexan diseases. Here we will review advances, as well as challenges and lessons learned regarding efficacy, safety, and pharmacology that have shaped our selection of pre-clinical candidates.
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http://dx.doi.org/10.1016/j.ijpara.2020.01.006DOI Listing
May 2020

In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae.

PLoS Negl Trop Dis 2019 08 5;13(8):e0007636. Epub 2019 Aug 5.

Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Germany.

Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4-6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti-Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia depletion kinetics with different regimens. Wolbachia reduction occurred in mice as early as 3 days after the initiation of ABBV-4083 treatment and continued throughout a 10-day treatment period. Importantly, Wolbachia levels continued to decline after a 5-day-treatment from 91.5% to 99.9% during a 3-week washout period. In jirds, two weeks of ABBV-4083 treatment (100mg/kg once-per-day) caused a >99.9% Wolbachia depletion in female adult worms, and the kinetics of Wolbachia depletion were recapitulated in peripheral blood microfilariae. Similar to Wolbachia depletion, inhibition of embryogenesis was time-dependent in ABBV-4083-treated jirds, leading to a complete lack of late embryonic stages (stretched microfilariae) and lack of peripheral microfilariae in 5/6 ABBV-4083-treated jirds by 14 weeks after treatment. Twice daily treatment in comparison to once daily treatment with ABBV-4083 did not significantly improve Wolbachia depletion. Moreover, up to 4 nonconsecutive daily treatments within a 14-dose regimen did not significantly erode Wolbachia depletion. Within the limitations of an animal model that does not fully recapitulate human filarial disease, our studies suggest that Wolbachia depletion should be assessed clinically no earlier than 3-4 weeks after the end of treatment, and that Wolbachia depletion in microfilariae may be a viable surrogate marker for the depletion within adult worms. Furthermore, strict daily adherence to the dosing regimen with anti-Wolbachia candidates may not be required, provided that the full regimen is subsequently completed.
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http://dx.doi.org/10.1371/journal.pntd.0007636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695197PMC
August 2019

Preclinical development of an oral anti- macrolide drug for the treatment of lymphatic filariasis and onchocerciasis.

Sci Transl Med 2019 03;11(483)

Global Pharmaceutical Research and Development, AbbVie, North Chicago, IL, USA.

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis ( and ) and onchocerciasis (). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti- macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.
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http://dx.doi.org/10.1126/scitranslmed.aau2086DOI Listing
March 2019

Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity.

PLoS Negl Trop Dis 2019 02 28;13(2):e0007159. Epub 2019 Feb 28.

Global Pharmaceutical Research and Development, AbbVie, North Chicago, Illinois, United States of America.

There is a significant need for improved treatments for onchocerciasis and lymphatic filariasis, diseases caused by filarial worm infection. In particular, an agent able to selectively kill adult worms (macrofilaricide) would be expected to substantially augment the benefits of mass drug administration (MDA) with current microfilaricides, and to provide a solution to treatment of onchocerciasis / loiasis co-infection, where MDA is restricted. We have identified a novel macrofilaricidal agent, Tylosin A (TylA), which acts by targeting the worm-symbiont Wolbachia bacterium. Chemical modification of TylA leads to improvements in anti-Wolbachia activity and oral pharmacokinetic properties; an optimized analog (ABBV-4083) has been selected for clinical evaluation.
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http://dx.doi.org/10.1371/journal.pntd.0007159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413952PMC
February 2019

Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine.

J Med Chem 2018 06 11;61(12):5138-5153. Epub 2018 Jun 11.

Laboratory of Peptide Sciences , Nagahama Institute of Bio-Science and Technology , Nagahama 526-0829 , Japan.

The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P, P, and Ṕ moieties. The derivatives with P tetrahydrofuranylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01709DOI Listing
June 2018

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis.

Int J Parasitol 2017 10 9;47(12):753-763. Epub 2017 Sep 9.

Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington, Seattle, WA 98109, USA. Electronic address:

Improvements have been made to the safety and efficacy of bumped kinase inhibitors, and they are advancing toward human and animal use for treatment of cryptosporidiosis. As the understanding of bumped kinase inhibitor pharmacodynamics for cryptosporidiosis therapy has increased, it has become clear that better compounds for efficacy do not necessarily require substantial systemic exposure. We now have a bumped kinase inhibitor with reduced systemic exposure, acceptable safety parameters, and efficacy in both the mouse and newborn calf models of cryptosporidiosis. Potential cardiotoxicity is the limiting safety parameter to monitor for this bumped kinase inhibitor. This compound is a promising pre-clinical lead for cryptosporidiosis therapy in animals and humans.
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http://dx.doi.org/10.1016/j.ijpara.2017.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772984PMC
October 2017

Crystal structure of full-length Zika virus NS5 protein reveals a conformation similar to Japanese encephalitis virus NS5.

Acta Crystallogr F Struct Biol Commun 2017 03 21;73(Pt 3):116-122. Epub 2017 Feb 21.

AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.

The rapid spread of the recent Zika virus (ZIKV) epidemic across various countries in the American continent poses a major health hazard for the unborn fetuses of pregnant women. To date, there is no effective medical intervention. The nonstructural protein 5 of Zika virus (ZIKV-NS5) is critical for ZIKV replication through the 5'-RNA capping and RNA polymerase activities present in its N-terminal methyltransferase (MTase) and C-terminal RNA-dependent RNA polymerase (RdRp) domains, respectively. The crystal structure of the full-length ZIKV-NS5 protein has been determined at 3.05 Å resolution from a crystal belonging to space group P222 and containing two protein molecules in the asymmetric unit. The structure is similar to that reported for the NS5 protein from Japanese encephalitis virus and suggests opportunities for structure-based drug design targeting either its MTase or RdRp domain.
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http://dx.doi.org/10.1107/S2053230X17001601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349304PMC
March 2017

Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis.

ACS Infect Dis 2017 01 17;3(1):18-33. Epub 2016 Oct 17.

Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee , Dundee DD1 5EH, United Kingdom.

A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.
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http://dx.doi.org/10.1021/acsinfecdis.6b00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972394PMC
January 2017

Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.

J Med Chem 2016 07 1;59(13):6531-46. Epub 2016 Jul 1.

Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.

New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100899PMC
July 2016

A specific inhibitor of PfCDPK4 blocks malaria transmission: chemical-genetic validation.

J Infect Dis 2014 Jan 10;209(2):275-84. Epub 2013 Oct 10.

Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle.

Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is critical in reducing or eliminating malaria in endemic regions. Here, we report the pharmacological characterization of a new class of malaria transmission-blocking compounds that acts via the inhibition of Plasmodia CDPK4 enzyme. We demonstrate that these compounds achieved selectivity over mammalian kinases by capitalizing on a small serine gatekeeper residue in the active site of the Plasmodium CDPK4 enzyme. To directly confirm the mechanism of action of these compounds, we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147 M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains in the presence of compound 1294, providing chemical-genetic evidence that CDPK4 is the target of the compound. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials such as artemisinin combination therapy (ACT) is a promising option for drug delivery that may reduce transmission of malaria including drug-resistant strains. Ongoing studies include refining the compounds to improve efficacy and toxicological properties for efficient blocking of malaria transmission.
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http://dx.doi.org/10.1093/infdis/jit522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873787PMC
January 2014

Discovery of pyrido[2,3-d]pyrimidine-based inhibitors of HCV NS5A.

Bioorg Med Chem Lett 2013 Jun 10;23(12):3627-30. Epub 2013 Apr 10.

Research and Development, AbbVie Inc., North Chicago, IL 60064, USA.

Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional 'E' ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series.
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http://dx.doi.org/10.1016/j.bmcl.2013.04.009DOI Listing
June 2013

Novel hepatitis C virus replicon inhibitors: synthesis and structure-activity relationships of fused pyrimidine derivatives.

Bioorg Med Chem Lett 2012 Mar 2;22(6):2212-5. Epub 2012 Feb 2.

Abbott Labs, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA.

The synthesis of several pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine analogs is described with one such analog possessing subnanomolar potency in both genotype 1a and 1b cell culture HCV replicon assays.
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http://dx.doi.org/10.1016/j.bmcl.2012.01.096DOI Listing
March 2012

P1-substituted symmetry-based human immunodeficiency virus protease inhibitors with potent antiviral activity against drug-resistant viruses.

J Med Chem 2011 Oct 21;54(20):7094-104. Epub 2011 Sep 21.

Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, United States.

Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.
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http://dx.doi.org/10.1021/jm201109tDOI Listing
October 2011

Hepatitis C NS5B polymerase inhibitors: functional equivalents for the benzothiadiazine moiety.

Bioorg Med Chem Lett 2011 Mar 13;21(6):1876-9. Epub 2011 Jan 13.

Department of Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.

A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays.
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http://dx.doi.org/10.1016/j.bmcl.2010.12.067DOI Listing
March 2011

Prevalence, mutation patterns, and effects on protease inhibitor susceptibility of the L76V mutation in HIV-1 protease.

Antimicrob Agents Chemother 2010 Nov 30;54(11):4903-6. Epub 2010 Aug 30.

Abbott Molecular, 1300 East Touhy Avenue, Des Plaines, IL 60018-3315, USA.

Patterns of HIV-1 protease inhibitor (PI) resistance-associated mutations (RAMs) and effects on PI susceptibility associated with the L76V mutation were studied in a large database. Of 20,501 sequences with ≥1 PI RAM, 3.2% contained L76V; L76V was alone in 0.04%. Common partner mutations included M46I, I54V, V82A, I84V, and L90M. L76V was associated with a 2- to 6-fold decrease in susceptibility to lopinavir, darunavir, amprenavir, and indinavir and a 7- to 8-fold increase in susceptibility to atazanavir and saquinavir.
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http://dx.doi.org/10.1128/AAC.00906-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976162PMC
November 2010

Liver transcriptomic changes associated with ritonavir-induced hyperlipidemia in sensitive and resistant strains of rats.

Vet J 2010 Jul 23;185(1):75-82. Epub 2010 May 23.

Abbott Laboratories, Abbott Park, IL, USA.

Ritonavir (RTV) and other protease inhibitors (PIs) used for the treatment of human immunodeficiency virus (HIV) infection are associated with elevated serum triglycerides (TG) and cholesterol in some patients. A rat strain (Sprague-Dawley or SD) commonly used in toxicology studies is not sensitive to RTV-induced hyperlipidemia, making mechanistic studies and the identification of novel, lipid-neutral PIs challenging. The objective of this study was to identify a rat strain that mirrors human PI-associated hyperlipidemia. RTV was administered at 100 mg/kg/day for 5 days to a panel of 14 rat strains estimated to cover approximately 86% of the known genetic variance in rats. Increased serum TG and cholesterol levels occurred only in two rat strains, including LEW x BN rats. Livers from LEW x BN (sensitive) and SD (resistant) rats were then evaluated using microarrays to investigate differences in the transcriptomic response to RTV. Several genes, including some involved in bile acid biosynthesis, gluconeogenesis, and carbohydrate metabolism, were differentially regulated between the two strains. In particular, cytochrome P450 7A1 (CYP7A1), a key enzyme for cholesterol metabolism, was down-regulated in the sensitive and up-regulated in resistant rats. Collectively, these results demonstrate the utility of a genetically diverse rat panel to identify strains with clinical relevance for a particular adverse effect. Furthermore, the genome-wide transcriptomic analysis suggests that RTV-induced hyperlipidemia is at least in part due to changes in hepatic lipid biosynthesis and metabolism. These findings will facilitate the discovery of novel, lipid-neutral HIV PIs and the identification of relevant biomarkers for this adverse event.
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http://dx.doi.org/10.1016/j.tvjl.2010.04.017DOI Listing
July 2010

Identification of proteasome gene regulation in a rat model for HIV protease inhibitor-induced hyperlipidemia.

Arch Toxicol 2010 Apr 6;84(4):263-70. Epub 2010 Mar 6.

Abbott Laboratories Global Pharmaceuticals Research and Development, 100 Abbott Park Rd, Abbott Park, IL 60064-6123, USA.

Patients treated with highly active antiretroviral therapy may develop metabolic side effects such as hyperlipidemia, insulin resistance, lipoatrophy and lactic acidosis. The pathophysiology of these metabolic abnormalities is unknown, although some, e.g., lactic acidosis and lipoatrophy, are more associated with nucleoside use while protease inhibitors (PIs) have been shown to contribute to hyperlipidemia and insulin resistance. Identifying new PIs that are not associated with dyslipidemia has been hindered by the lack of mechanistic information and the unavailability of relevant animal models. In order to understand the molecular mechanism behind the hyperlipidemia associated with other protease inhibitors, and to develop a more effective, faster screen for compounds with this liability, we have analyzed expression profiles from PI-treated animals. Previously, we have shown that treatment of rats with ritonavir results in increases in the expression of proteasomal subunit genes in the liver. We show this increase is similar in rats treated with bortezomib, a proteasome inhibitor. In addition, we have treated rats with additional protease inhibitors, including atazanavir, which is associated with lower rates of lipid elevations in the clinic when administered in the absence of ritonavir. Our results indicate a strong correlation between proteasomal induction and lipid elevations, and have allowed us to develop a rapid screen for identifying novel PIs that do not induce the proteasome.
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http://dx.doi.org/10.1007/s00204-010-0527-7DOI Listing
April 2010

Non-peptide entry inhibitors of HIV-1 that target the gp41 coiled coil pocket.

Bioorg Med Chem Lett 2010 Jan 20;20(2):612-7. Epub 2009 Nov 20.

Pharmaceutical Discovery Division, Abbott Laboratories, 100 Abbott Park Rd., R46Y, AP10, Abbott Park, IL 60064-6098, United States.

The ectodomain of HIV-1 gp41 mediates the fusion of viral and host cellular membranes. The peptide-based drug Enfuvirtide(1) is precedent that antagonists of this fusion activity may act as anti HIV-agents. Here, NMR screening was used to discover non-peptide leads against this target and resulted in the discovery of a new benzamide 1 series. This series is non-peptide, low molecular weight, and analogs have activity in a cell fusion assay with EC50 values ranging 3-41microM. Structural work on the gp41/benzamide 1 complex was determined by NMR spectroscopy using a designed model peptide system that mimics an open pocket of the fusogenic form of the protein.
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http://dx.doi.org/10.1016/j.bmcl.2009.11.076DOI Listing
January 2010

Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket.

J Med Chem 2009 Dec;52(23):7604-17

Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.

A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P(2)' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate 1 (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of an anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity. X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group at P(2)' position revealed hydrophobic interactions with Ala28, Ile84, and Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.
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http://dx.doi.org/10.1021/jm9005115DOI Listing
December 2009

Synthesis and evaluation of inhibitors of cytochrome P450 3A (CYP3A) for pharmacokinetic enhancement of drugs.

Bioorg Med Chem Lett 2009 Sep 30;19(18):5444-8. Epub 2009 Jul 30.

Abbott Laboratories, Departments of Antiviral Research (D-R4CQ), Building AP-52, 200 Abbott Park Road, Abbott Park, IL 60064-3537, USA.

The HIV protease inhibitor ritonavir (RTV) is also a potent inhibitor of the metabolizing enzyme cytochrome P450 3A (CYP3A) and is clinically useful in HIV therapy in its ability to enhance human plasma levels of other HIV protease inhibitors (PIs). A novel series of CYP3A inhibitors was designed around the structural elements of RTV believed to be important to CYP3A inhibition, with general design features being the attachment of groups that mimic the P2-P3 segment of RTV to a soluble core. Several analogs were found to strongly enhance plasma levels of lopinavir (LPV), including 8, which compares favorably with RTV in the same model. Interestingly, an inverse correlation between in vitro inhibition of CYP3A and elevation of LPV was observed. The compounds described in this study may be useful for enhancing the pharmacokinetics of drugs that are metabolized by CYP3A.
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http://dx.doi.org/10.1016/j.bmcl.2009.07.118DOI Listing
September 2009

Synthesis and biological characterization of B-ring amino analogues of potent benzothiadiazine hepatitis C virus polymerase inhibitors.

J Med Chem 2009 May;52(10):3174-83

Global Pharmaceutical Research and Development, Abbott, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA.

Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class of non-nucleoside inhibitors that have received considerable attention in the search for novel HCV therapeutics. Research in our laboratories has identified a novel series of tetracyclic benzothiadiazine inhibitors of HCV polymerase bearing a benzylamino substituent on the B-ring. Compounds in this series exhibit low-nanomolar activities in both genotypes 1a and 1b polymerase inhibition assays and subgenomic replicon assays. Optimization of pharmacokinetic properties in rat led to compound 30, which has good oral bioavailability (F = 56%) and a favorable tissue distribution drug profile, with high liver to plasma ratios. Compound 30 is a potent inhibitor in replicon assays, with EC(50) values of 10 and 6 nM against genotypes 1a and 1b, respectively.
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http://dx.doi.org/10.1021/jm801485zDOI Listing
May 2009

Water-soluble prodrugs of the human immunodeficiency virus protease inhibitors lopinavir and ritonavir.

J Med Chem 2009 May;52(9):2964-70

Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.

We studied the synthesis, cleavage rates, and oral administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of the parent drugs in vivo. However, oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the solid prodrugs led to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited solubility.
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http://dx.doi.org/10.1021/jm900080gDOI Listing
May 2009

2-Pyridyl P1'-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and A-790742) with potential for convenient dosing and reduced side effects.

J Med Chem 2009 Apr;52(8):2571-86

Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.

A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.
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http://dx.doi.org/10.1021/jm900044wDOI Listing
April 2009

Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines.

J Med Chem 2009 Mar;52(6):1659-69

Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064, USA.

The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
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http://dx.doi.org/10.1021/jm8010965DOI Listing
March 2009

Hepatitis C NS5B polymerase inhibitors: 4,4-Dialkyl-1-hydroxy-3-oxo-3,4-dihydronaphthalene-3-yl benzothiadiazine derivatives.

Bioorg Med Chem Lett 2008 Jul 18;18(14):3887-90. Epub 2008 Jun 18.

Department of Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.

4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.
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http://dx.doi.org/10.1016/j.bmcl.2008.06.043DOI Listing
July 2008

Synthesis, antiviral activity, and conformational studies of a P3 aza-peptide analog of a potent macrocyclic tripeptide HCV protease inhibitor.

Bioorg Med Chem Lett 2008 Apr 26;18(8):2745-50. Epub 2008 Feb 26.

Global Pharmaceutical Research and Development, Antiviral Research, 200 Abbott Park Road, Abbott Park, IL 60064, USA.

BILN 2061 is a macrocyclic tripeptide inhibitor of hepatitis C virus NS3-4A protease that has shown efficacy in the clinic for treating patients infected with HCV. We have synthesized a P3 aza-peptide analog of a potent macrocyclic tripeptide inhibitor closely related to BILN 2061. This aza-derivative was found to be >2 orders of magnitude less active than the parent macrocycle in both isolated enzyme (HCV NS3-4A) and HCV subgenomic replicon assays. NMR studies of P3 aza-peptides revealed these compounds adopt a beta-turn conformation stabilized by an intramolecular H-bonding interaction. Molecular models of these structures indicate a D-like configuration of the P3 aza-residue. Thus, the configurationally undefined nature at P3 in the aza-peptide allows the compound to adopt an H-bond stabilized conformation that is substantially different from that necessary for tight binding to the active site of HCV NS3 protease.
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http://dx.doi.org/10.1016/j.bmcl.2008.02.053DOI Listing
April 2008

Des-A-ring benzothiadiazines: inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase.

Bioorg Med Chem Lett 2008 Apr 4;18(8):2735-8. Epub 2008 Mar 4.

Antiviral Research, Global Pharmaceutical Research, and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.

In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure-activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies.
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http://dx.doi.org/10.1016/j.bmcl.2008.02.064DOI Listing
April 2008