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Article: Fluorinated Isoindolinone-Based Glucosylceramide Synthase Inhibitors with Low Human Dose Projections.

Loughran, H Marie / Schirripa, Kathy M / Roecker, Anthony J / Breslin, Michael J / Tong, Ling / Fillgrove, Kerry L / Kuo, Yuhsin / Bleasby, Kelly / Collier, Hannah / Altman, Michael D / Ford, Melissa C / Newman, Justin A / Drolet, Robert E / Cosden, Mali / Jinn, Sarah / Flick, Rosemarie B / Liu, Xiaomei / Minnick, Christina / Watt, Marla L /

Lemaire, Wei / Burlein, Christine / Adam, Gregory C / Austin, Lauren A / Marcus, Jacob N / Smith, Sean M / Fraley, Mark E

ACS medicinal chemistry letters

2023 Volume 15, Issue 1, Page(s) 123–131

Abstract: Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing ...

Abstract	Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.3c00436
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Article: Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease.

Roecker, Anthony J / Schirripa, Kathy M / Loughran, H Marie / Tong, Ling / Liang, Tao / Fillgrove, Kerry L / Kuo, Yuhsin / Bleasby, Kelly / Collier, Hannah / Altman, Michael D / Ford, Melissa C / Drolet, Robert E / Cosden, Mali / Jinn, Sarah / Hatcher, Nathan G / Yao, Lihang / Kandebo, Monika / Vardigan, Joshua D / Flick, Rosemarie B /

Liu, Xiaomei / Minnick, Christina / Price, Laura A / Watt, Marla L / Lemaire, Wei / Burlein, Christine / Adam, Gregory C / Austin, Lauren A / Marcus, Jacob N / Smith, Sean M / Fraley, Mark E

ACS medicinal chemistry letters

2023 Volume 14, Issue 2, Page(s) 146–155

Abstract: Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme ... ...

Abstract	Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with
Language	English
Publishing date	2023-01-12
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.2c00441
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Article ; Online: Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress.

Loughran, H Marie / Han, Ziying / Wrobel, Jay E / Decker, Sarah E / Ruthel, Gordon / Freedman, Bruce D / Harty, Ronald N / Reitz, Allen B

Bioorganic & medicinal chemistry letters

2016 Volume 26, Issue 15, Page(s) 3429–3435

Abstract: We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular ... ...

Abstract	We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular complementation assay (BiMC) to detect and visualize a Marburg mVP40-Nedd4 interaction in live mammalian cells. Antiviral activity was assessed for selected compounds using a live recombinant vesicular stomatitis virus (VSV) (M40 virus) that expresses the EBOV VP40 PPxY L-domain. Finally selected compounds were evaluated in several ADME assays to have an early assessment of their drug properties. Our compounds had low nM potency in these assays (e.g., compounds 21, 24, 26, 39), and had good human liver microsome stability, as well as little or no inhibition of P450 3A4.
MeSH term(s)	Animals ; Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 CYP3A Inhibitors/chemical synthesis ; Cytochrome P-450 CYP3A Inhibitors/chemistry ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Dose-Response Relationship, Drug ; Ebolavirus/chemistry ; HEK293 Cells ; Humans ; Marburgvirus/chemistry ; Mice ; Microbial Sensitivity Tests ; Microsomes, Liver/chemistry ; Microsomes, Liver/metabolism ; Molecular Structure ; Quinoxalines/chemical synthesis ; Quinoxalines/chemistry ; Quinoxalines/pharmacology ; Structure-Activity Relationship ; Vesicular stomatitis Indiana virus/drug effects ; Viral Matrix Proteins/antagonists & inhibitors
Chemical Substances	Antiviral Agents ; Cytochrome P-450 CYP3A Inhibitors ; Quinoxalines ; VP40 protein, virus ; Viral Matrix Proteins ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55)
Language	English
Publishing date	2016-06-23
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2016.06.053
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Article ; Online: Synthesis and evaluation of orally active small molecule HIV-1 Nef antagonists.

Emert-Sedlak, Lori A / Loughran, H Marie / Shi, Haibin / Kulp, John L / Shu, Sherry T / Zhao, Jielu / Day, Billy W / Wrobel, Jay E / Reitz, Allen B / Smithgall, Thomas E

Bioorganic & medicinal chemistry letters

2016 Volume 26, Issue 5, Page(s) 1480–1484

Abstract: The HIV-1 Nef accessory factor enhances viral replication and promotes immune system evasion of HIV-infected cells, making it an attractive target for drug discovery. Recently we described a novel class of diphenylpyrazolodiazene compounds that bind ... ...

Abstract	The HIV-1 Nef accessory factor enhances viral replication and promotes immune system evasion of HIV-infected cells, making it an attractive target for drug discovery. Recently we described a novel class of diphenylpyrazolodiazene compounds that bind directly to Nef in vitro and inhibit Nef-dependent HIV-1 infectivity and replication in cell culture. However, these first-generation Nef antagonists have several structural liabilities, including an azo linkage that led to poor oral bioavailability. The azo group was therefore replaced with either a one- or two-carbon linker. The resulting set of non-azo analogs retained nanomolar binding affinity for Nef by surface plasmon resonance, while inhibiting HIV-1 replication with micromolar potency in cell-based assays without cytotoxicity. Computational docking studies show that these non-azo analogs occupy the same predicted binding site within the HIV-1 Nef dimer interface as the original azo compound. Computational methods also identified a hot spot for inhibitor binding within this site that is defined by conserved HIV-1 Nef residues Asp108, Leu112, and Pro122. Pharmacokinetic evaluation of the non-azo B9 analogs in mice showed that replacement of the azo linkage dramatically enhanced oral bioavailability without substantially affecting plasma half-life or clearance. The improved oral bioavailability of non-azo diphenylpyrazolo Nef antagonists provides a starting point for further drug lead optimization in support of future efficacy testing in animal models of HIV/AIDS.
MeSH term(s)	Administration, Oral ; Animals ; Anti-HIV Agents/administration & dosage ; Anti-HIV Agents/chemical synthesis ; Anti-HIV Agents/pharmacology ; Binding Sites/drug effects ; Dose-Response Relationship, Drug ; HIV-1/drug effects ; Mice ; Microbial Sensitivity Tests ; Models, Molecular ; Molecular Conformation ; Molecular Docking Simulation ; Small Molecule Libraries/administration & dosage ; Small Molecule Libraries/chemical synthesis ; Small Molecule Libraries/pharmacology ; Structure-Activity Relationship ; Tumor Cells, Cultured ; Virus Replication/drug effects ; nef Gene Products, Human Immunodeficiency Virus/antagonists & inhibitors
Chemical Substances	Anti-HIV Agents ; Small Molecule Libraries ; nef Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2016-01-21
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2016.01.043
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Article ; Online: Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents.

Rubin, Harvey / Selwood, Trevor / Yano, Takahiro / Weaver, Damian G / Loughran, H Marie / Costanzo, Michael J / Scott, Richard W / Wrobel, Jay E / Freeman, Katie B / Reitz, Allen B

Bioorganic & medicinal chemistry letters

2014 Volume 25, Issue 2, Page(s) 378–383

Abstract: The Gram-negative bacterium Acinetobacter baumannii is an opportunistic pathogen in humans and infections are poorly treated by current therapy. Recent emergence of multi-drug resistant strains and the lack of new antibiotics demand an immediate action ... ...

Abstract	The Gram-negative bacterium Acinetobacter baumannii is an opportunistic pathogen in humans and infections are poorly treated by current therapy. Recent emergence of multi-drug resistant strains and the lack of new antibiotics demand an immediate action for development of new anti-Acinetobacter agents. To this end, oxidative phosphorylation (OxPhos) was identified as a novel target for drug discovery research. Consequently, a library of ∼10,000 compounds was screened using a membrane-based ATP synthesis assay. One hit identified was the 2-iminobenzimidazole 1 that inhibited the OxPhos of A. baumannii with a modestly high selectivity against mitochondrial OxPhos, and displayed an MIC of 25μM (17μg/mL) against the pathogen. The 2-iminobenzimidazole 1 was found to inhibit the type 1 NADH-quinone oxidoreductase (NDH-1) of A. baumannii OxPhos by a biochemical approach. Among various derivatives that were synthesized to date, des-hydroxy analog 5 is among the most active with a relatively tight SAR requirement for the N'-aminoalkyl side chain. Analog 5 also showed less cytotoxicity against NIH3T3 and HepG2 mammalian cell lines, demonstrating the potential for this series of compounds as anti-Acinetobacter agents. Additional SAR development and target validation is underway.
MeSH term(s)	Acinetobacter Infections/drug therapy ; Acinetobacter Infections/microbiology ; Acinetobacter baumannii/drug effects ; Animals ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Benzimidazoles/chemistry ; Benzimidazoles/pharmacology ; Cell Proliferation/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/pathology ; Mice ; Microbial Sensitivity Tests ; Molecular Structure ; NIH 3T3 Cells ; Oxidative Phosphorylation/drug effects ; Quinone Reductases/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Structure-Activity Relationship
Chemical Substances	Anti-Bacterial Agents ; Antineoplastic Agents ; Benzimidazoles ; Small Molecule Libraries ; NADH dehydrogenase (quinone) (EC 1.6.5.11) ; Quinone Reductases (EC 1.6.99.-)
Language	English
Publishing date	2014-11-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2014.11.020
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Article: Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors.

Bungard, Christopher J / Williams, Peter D / Schulz, Jurgen / Wiscount, Catherine M / Holloway, M Katharine / Loughran, H Marie / Manikowski, Jesse J / Su, Hua-Poo / Bennett, David J / Chang, Lehua / Chu, Xin-Jie / Crespo, Alejandro / Dwyer, Michael P / Keertikar, Kartik / Morriello, Gregori J / Stamford, Andrew W / Waddell, Sherman T / Zhong, Bin / Hu, Bin /

Ji, Tao / Diamond, Tracy L / Bahnck-Teets, Carolyn / Carroll, Steven S / Fay, John F / Min, Xu / Morris, William / Ballard, Jeanine E / Miller, Michael D / McCauley, John A

ACS medicinal chemistry letters

2017 Volume 8, Issue 12, Page(s) 1292–1297

Abstract: Using the HIV-1 protease binding mode ... ...

Abstract	Using the HIV-1 protease binding mode of
Language	English
Publishing date	2017-11-13
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.7b00386
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Article ; Online: Structural basis for the inhibition of RNase H activity of HIV-1 reverse transcriptase by RNase H active site-directed inhibitors.

Su, Hua-Poo / Yan, Youwei / Prasad, G Sridhar / Smith, Robert F / Daniels, Christopher L / Abeywickrema, Pravien D / Reid, John C / Loughran, H Marie / Kornienko, Maria / Sharma, Sujata / Grobler, Jay A / Xu, Bei / Sardana, Vinod / Allison, Timothy J / Williams, Peter D / Darke, Paul L / Hazuda, Daria J / Munshi, Sanjeev

Journal of virology

2010 Volume 84, Issue 15, Page(s) 7625–7633

Abstract: HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms ...

Abstract	HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.
MeSH term(s)	Binding Sites ; Catalytic Domain ; Cations/metabolism ; Crystallography, X-Ray ; Enzyme Inhibitors/metabolism ; HIV ; HIV Reverse Transcriptase/antagonists & inhibitors ; HIV Reverse Transcriptase/chemistry ; HIV Reverse Transcriptase/metabolism ; HIV-1/chemistry ; HIV-1/drug effects ; Humans ; Metals/metabolism ; Models, Molecular ; Naphthyridines/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Ribonuclease H, Human Immunodeficiency Virus/antagonists & inhibitors ; Ribonuclease H, Human Immunodeficiency Virus/chemistry ; Ribonuclease H, Human Immunodeficiency Virus/metabolism
Chemical Substances	Cations ; Enzyme Inhibitors ; Metals ; Naphthyridines ; reverse transcriptase, Human immunodeficiency virus 1 (EC 2.7.7.-) ; HIV Reverse Transcriptase (EC 2.7.7.49) ; Ribonuclease H, Human Immunodeficiency Virus (EC 3.1.26.4)
Language	English
Publishing date	2010-05-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00353-10
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Article ; Online: Potent and selective HIV-1 ribonuclease H inhibitors based on a 1-hydroxy-1,8-naphthyridin-2(1H)-one scaffold.

Bioorganic & medicinal chemistry letters

2010 Volume 20, Issue 22, Page(s) 6754–6757

Abstract: Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective inhibitors. The best compound was potent and selective in ...

Abstract	Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective inhibitors. The best compound was potent and selective in biochemical assays (IC(50)=0.045 μM, HIV RT RNase H; 13 μM, HIV RT-polymerase; 24 μM, HIV integrase) and showed antiviral efficacy in a single-cycle viral replication assay in P4-2 cells (IC(50)=0.19 μM) with a modest window with respect to cytotoxicity (CC(50)=3.3 μM).
MeSH term(s)	Anti-HIV Agents/chemistry ; Anti-HIV Agents/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; HIV-1/enzymology ; HeLa Cells ; Humans ; Naphthyridines/chemistry ; Naphthyridines/pharmacology ; Ribonuclease H/antagonists & inhibitors
Chemical Substances	1-hydroxy-1,8-naphthyridin-2(1H)-one ; Anti-HIV Agents ; Enzyme Inhibitors ; Naphthyridines ; Ribonuclease H (EC 3.1.26.4)
Language	English
Publishing date	2010-11-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2010.08.135
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