2017年6月4日日曜日

IOO1+P2H7 Dual Inhibitors 2017

http://www.sciencedirect.com/science/article/pii/S1074761316300541

Heme dioxygenases are a family of enzymes that include indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2), as well as tryptophan 2,3-dioxygenase (TDO).

These catalyze the initial and rate-limiting step of tryptophan degradation in the kynurenine pathway:

L-tryptophan + O2 -> N-formyl-L-kynuren (Munn and Mellor, 2013).

IDO1 expression is induced by various agonists in macrophages while TDO is expressed mainly in parenchyma cells (Munn and Mellor, 2013).

The product of heme dioxygenases, i.e., N-formyl-L-kynuren, is sensed in macrophages via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that modulates macrophage activation (Bessede et al., 2014; Stockinger et al., 2014).

Heme-iron metabolism can regulate this signal transduction pathway at different levels: (i) restricting heme availability for expression and activity of heme dioxygenases; (ii) Modulating enzymatic activity via CO binding to ferrous heme (Brady, 1975), or (iii) via the production of biliverdin, an end product of heme catabolism by HO-1 sensed by AhR (Phelan et al., 1998).

Given the central role played by AhR in the regulation of both macrophage and T cell activation, modulation of this pathway by heme-iron catabolism is likely to impact macrophage and/or T cell activation. This remains however to be tested experimentally.

Reevaluating the role of IDO1: Examining NAD + metabolism in inflammation

Peter Kim Moon ^a,
Paras Singh Minhas ^b^,^,

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https://doi.org/10.1016/j.jneuroim.2017.03.016

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Highlights

•: Indoleamine-2,3-dioxygenase (IDO1) upregulation may generate de novo NAD +.
•: De novo NAD + provides increased substrate to increase Complex I – IV activities within mitochondria.
•: Examining kynurenine pathway and NAD + metabolism within the CNS is necessary to examine the potential impacts of IDO1.

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: Corresponding author at: Department of Neurology & Neurological Sciences, 1201 Welch Road, MSLS P250, Stanford, CA 94305, United States.

2017年6月3日土曜日

Article

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

Andrew M. Thompson^*^†

, Patrick D. O’Connor^†, Andrew J. Marshall^†, Vanessa Yardley^‡, Louis Maes^§, Suman Gupta^∥, Delphine Launay^⊥, Stephanie Braillard^⊥, Eric Chatelain^⊥, Scott G. Franzblau^#, Baojie Wan^#, Yuehong Wang^#, Zhenkun Ma^∇, Christopher B. Cooper^∇, and William A. Denny^†

^† Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

^‡ Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom

^§ Laboratory for Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium

^∥ Division of Parasitology, CSIR—Central Drug Research Institute, Lucknow 226031, India

^⊥ Drugs for Neglected Diseases initiative, 15 Chemin Louis Dunant, 1202 Geneva, Switzerland

^# Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States

^∇ Global Alliance for TB Drug Development, 40 Wall Street, New York 10005, United States

J. Med. Chem., 2017, 60 (10), pp 4212–4233

DOI: 10.1021/acs.jmedchem.7b00034

Publication Date (Web): May 1, 2017

*Phone: (+649) 923-6145. Fax: (+649) 373-7502. E-mail: am.thompson@auckland.ac.nz.

Abstract

Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00034.

Additional biological assay data, synthetic schemes, graphs of PK and assay data, experimental procedures and characterizations for compounds, combustion analytical data, and representative NMR spectra (PDF)
Molecular formula strings spreadsheet (CSV)

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Related Content

Nitroimidazoles 2017 Reviews

For the Recent Nitroimidazole Medicinal Chemistry Avenues;

Perspective

Nitroimidazoles: Molecular Fireworks That Combat a Broad Spectrum of Infectious Diseases

Chee Wei Ang, Angie M. Jarrad‡, Matthew A. Cooper

, and Mark A. T. Blaskovich^*

The Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.7b00143

Publication Date (Web): May 2, 2017

*Phone: +61 7 3346 2045. E-mail: m.blaskovich@uq.edu.au.

Abstract

Infectious diseases claim millions of lives every year, but with the advent of drug resistance, therapeutic options to treat infections are inadequate. There is now an urgent need to develop new and effective treatments. Nitroimidazoles are a class of antimicrobial drugs that have remarkable broad spectrum activity against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. While nitroimidazoles were discovered in the 1950s, there has been renewed interest in their therapeutic potential, particularly for the treatment of parasitic infections and tuberculosis. In this review, we summarize different classes of nitroimidazoles that have been described in the literature in the past five years, from approved drugs and clinical candidates to examples undergoing preclinical or early stage development. The relatively “nonspecific” mode of action and resistance mechanisms of nitromidazoles are discussed, and contemporary strategies to facilitate nitroimidazole drug development are highlighted.

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2017年5月31日水曜日

Epacadostat for Immuno-Oncology 2017

See For Examples;

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721772/

A more recent study has demonstrated that P2X7 knockout mice show reduced pain sensitivity following both complete Freund’s adjuvant-induced inflammation and partial injury of the sciatic nerve [32].

These data were consistent with the mechanistic role of P2X7 receptors in modulating IL-1β release and the ability of IL-1β to alter pain sensitivity in experimental models.

It has been shown, for example, that increased IL-1 levels are associated with enhanced nociceptive signaling in a concentration-related fashion [33, 34].

The P2X7 receptor has also been linked with release of the excitatory neurotransmitter glutamate, well-known for its involvement in pain transmission. In hippocampal slices from P2X7 KO mice, ATP-evoked release of [3H]glutamate was virtually absent, in contrast to the robust neurotransmitter release observed with wild-type controls [35].

Under electrical stimulation, [3H]glutamate release was also significantly attenuated in the KO animals, although some level of residual release was present. These observations are consistent with results implicating the participation of P2X7 in excitatory amino acid release from murine astrocytes [36].

The potential role of P2X7 in modulating glutamate release thus provides an additional rationale for the reduced nociceptive responses of the P2X7 KO mice under chronic inflammation or nerve injury conditions.

In view of the participation of P2X7 in the release of IL-1β and glutamate, the localization of P2X7 receptors on glial cells, and the growing appreciation for the role of activated glia in promoting the development and maintenance of pathological pain [37–39], it is tempting to regard the P2X7 receptor as a central player in this neuroimmune interface.

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2017年6月4日日曜日

Heme dioxygenases are a family of enzymes that include indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2), as well as tryptophan 2,3-dioxygenase (TDO).

These catalyze the initial and rate-limiting step of tryptophan degradation in the kynurenine pathway:

L-tryptophan + O2 -> N-formyl-L-kynuren (Munn and Mellor, 2013).

IDO1 expression is induced by various agonists in macrophages while TDO is expressed mainly in parenchyma cells (Munn and Mellor, 2013).

The product of heme dioxygenases, i.e., N-formyl-L-kynuren, is sensed in macrophages via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that modulates macrophage activation (Bessede et al., 2014; Stockinger et al., 2014).

Given the central role played by AhR in the regulation of both macrophage and T cell activation, modulation of this pathway by heme-iron catabolism is likely to impact macrophage and/or T cell activation. This remains however to be tested experimentally.

Reevaluating the role of IDO1: Examining NAD + metabolism in inflammation

Highlights

2017年6月3日土曜日

Article

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

Abstract

PDF

Other ACS content by these authors:

Related Content:

Perspective

Nitroimidazoles: Molecular Fireworks That Combat a Broad Spectrum of Infectious Diseases

Abstract

View: ACS ActiveView PDF | PDF | PDF w/ Links | Full Text HTML

Other ACS content by these authors:

Related Content:

2017年5月31日水曜日

Epacadostat

See For Examples;

A more recent study has demonstrated that P2X7 knockout mice show reduced pain sensitivity following both complete Freund’s adjuvant-induced inflammation and partial injury of the sciatic nerve [32].

These data were consistent with the mechanistic role of P2X7 receptors in modulating IL-1β release and the ability of IL-1β to alter pain sensitivity in experimental models.

It has been shown, for example, that increased IL-1 levels are associated with enhanced nociceptive signaling in a concentration-related fashion [33, 34].

The potential role of P2X7 in modulating glutamate release thus provides an additional rationale for the reduced nociceptive responses of the P2X7 KO mice under chronic inflammation or nerve injury conditions.