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Article ; Online: Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies.

Soares de Melo, Candice / Singh, Vinayak / Myrick, Alissa / Simelane, Sandile B / Taylor, Dale / Brunschwig, Christel / Lawrence, Nina / Schnappinger, Dirk / Engelhart, Curtis A / Kumar, Anuradha / Parish, Tanya / Su, Qin / Myers, Timothy G / Boshoff, Helena I M / Barry, Clifton E / Sirgel, Frederick A / van Helden, Paul D / Buchanan, Kirsteen I / Bayliss, Tracy /

Green, Simon R / Ray, Peter C / Wyatt, Paul G / Basarab, Gregory S / Eyermann, Charles J / Chibale, Kelly / Ghorpade, Sandeep R

Journal of medicinal chemistry

2021 Volume 64, Issue 1, Page(s) 719–740

Abstract: Phenotypic screening of a Medicines for Malaria Venture compound library ... ...

Abstract	Phenotypic screening of a Medicines for Malaria Venture compound library against
MeSH term(s)	Animals ; Antitubercular Agents/chemistry ; Antitubercular Agents/metabolism ; Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Half-Life ; Humans ; Iron/metabolism ; Male ; Membrane Transport Proteins/genetics ; Membrane Transport Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Microbial Sensitivity Tests ; Microsomes/metabolism ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/isolation & purification ; Pyrazoles/chemistry ; Pyrimidinones/chemistry ; Pyrimidinones/metabolism ; Pyrimidinones/pharmacology ; Rats ; Structure-Activity Relationship
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; Membrane Transport Proteins ; MmpL3 protein, Mycobacterium tuberculosis ; Pyrazoles ; Pyrimidinones ; Iron (E1UOL152H7)
Language	English
Publishing date	2021-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c01727
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Green, Simon R / Davis, Susan H / Damerow, Sebastian / Engelhart, Curtis A / Mathieson, Michael / Baragaña, Beatriz / Robinson, David A / Tamjar, Jevgenia / Dawson, Alice / Tamaki, Fabio K / Buchanan, Kirsteen I / Post, John / Dowers, Karen / Shepherd, Sharon M / Jansen, Chimed / Zuccotto, Fabio / Gilbert, Ian H / Epemolu, Ola / Riley, Jennifer /

Stojanovski, Laste / Osuna-Cabello, Maria / Pérez-Herrán, Esther / Rebollo, María José / Guijarro López, Laura / Casado Castro, Patricia / Camino, Isabel / Kim, Heather C / Bean, James M / Nahiyaan, Navid / Rhee, Kyu Y / Wang, Qinglan / Tan, Vee Y / Boshoff, Helena I M / Converse, Paul J / Li, Si-Yang / Chang, Yong S / Fotouhi, Nader / Upton, Anna M / Nuermberger, Eric L / Schnappinger, Dirk / Read, Kevin D / Encinas, Lourdes / Bates, Robert H / Wyatt, Paul G / Cleghorn, Laura A T

Nature communications

2022 Volume 13, Issue 1, Page(s) 5992

Abstract: Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an ...

Abstract	Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.
MeSH term(s)	Animals ; Lysine-tRNA Ligase/chemistry ; Lysine-tRNA Ligase/genetics ; Lysine-tRNA Ligase/pharmacology ; Mice ; Mycobacterium tuberculosis/genetics ; Tuberculosis/drug therapy
Chemical Substances	Lysine-tRNA Ligase (EC 6.1.1.6)
Language	English
Publishing date	2022-10-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-33736-5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Pharmacokinetic optimisation of novel indole-2-carboxamide cannabinoid CB₁ antagonists

Cowley, Phillip M / Baker, James / Buchanan, Kirsteen I / Carlyle, Ian / Clark, John K / Clarkson, Thomas R / Deehan, Maureen / Edwards, Darren / Kiyoi, Yasuko / Martin, Iain / Osbourn, Dawn / Walker, Glenn / Ward, Nick / Wishart, Grant

Bioorganic & medicinal chemistry letters. 2011 Apr. 1, v. 21, no. 7

2011

Abstract: The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB₁ receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB₁ antagonist with high predicted human oral ...

Abstract	The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB₁ receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB₁ antagonist with high predicted human oral bioavailability.
Keywords	antagonists ; bioavailability ; cannabinoids ; humans ; pharmacokinetics ; receptors
Language	English
Dates of publication	2011-0401
Size	p. 2034-2039.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2011.02.019
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Pharmacokinetic optimisation of novel indole-2-carboxamide cannabinoid CB1 antagonists.

Bioorganic & medicinal chemistry letters

2011 Volume 21, Issue 7, Page(s) 2034–2039

Abstract: The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human ... ...

Abstract	The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.
MeSH term(s)	Administration, Oral ; Biological Availability ; Humans ; Indoles/administration & dosage ; Indoles/chemistry ; Indoles/pharmacokinetics ; Receptor, Cannabinoid, CB1/antagonists & inhibitors ; Structure-Activity Relationship
Chemical Substances	Indoles ; Receptor, Cannabinoid, CB1
Language	English
Publishing date	2011-04-01
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.2011.02.019
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Article ; Online: The discovery of novel indole-2-carboxamides as cannabinoid CB(1) receptor antagonists.

Cowley, Phillip M / Baker, James / Barn, David R / Buchanan, Kirsteen I / Carlyle, Ian / Clark, John K / Clarkson, Thomas R / Deehan, Maureen / Edwards, Darren / Goodwin, Richard R / Jaap, David / Kiyoi, Yasuko / Mort, Chris / Palin, Ronald / Prosser, Alan / Walker, Glenn / Ward, Nick / Wishart, Grant / Young, Trevor

Bioorganic & medicinal chemistry letters

2011 Volume 21, Issue 1, Page(s) 497–501

Abstract: The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist. ...

Abstract	The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
MeSH term(s)	Amides/chemical synthesis ; Amides/chemistry ; Amides/pharmacokinetics ; Animals ; Dogs ; Drug Evaluation, Preclinical ; Indoles/chemical synthesis ; Indoles/chemistry ; Indoles/pharmacokinetics ; Male ; Mice ; Models, Molecular ; Rats ; Rats, Wistar ; Receptor, Cannabinoid, CB1/antagonists & inhibitors ; Receptor, Cannabinoid, CB1/metabolism ; Structure-Activity Relationship
Chemical Substances	Amides ; Indoles ; Receptor, Cannabinoid, CB1
Language	English
Publishing date	2011-01-01
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.2010.10.104
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The discovery of novel indole-2-carboxamides as cannabinoid CB₁ receptor antagonists

Bioorganic & medicinal chemistry letters. 2011 Jan. 1, v. 21, no. 1

2011

Abstract: The discovery and structure–activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB₁ receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB₁ antagonist. ...

Abstract	The discovery and structure–activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB₁ receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB₁ antagonist.
Keywords	antagonists ; cannabinoids ; receptors ; structure-activity relationships
Language	English
Dates of publication	2011-0101
Size	p. 497-501.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2010.10.104
Database	NAL-Catalogue (AGRICOLA)

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

Park, Yumi / Pacitto, Angela / Bayliss, Tracy / Cleghorn, Laura A T / Wang, Zhe / Hartman, Travis / Arora, Kriti / Ioerger, Thomas R / Sacchettini, Jim / Rizzi, Menico / Donini, Stefano / Blundell, Tom L / Ascher, David B / Rhee, Kyu / Breda, Ardala / Zhou, Nian / Dartois, Veronique / Jonnala, Surendranadha Reddy / Via, Laura E /

Mizrahi, Valerie / Epemolu, Ola / Stojanovski, Laste / Simeons, Fred / Osuna-Cabello, Maria / Ellis, Lucy / MacKenzie, Claire J / Smith, Alasdair R C / Davis, Susan H / Murugesan, Dinakaran / Buchanan, Kirsteen I / Turner, Penelope A / Huggett, Margaret / Zuccotto, Fabio / Rebollo-Lopez, Maria Jose / Lafuente-Monasterio, Maria Jose / Sanz, Olalla / Diaz, Gracia Santos / Lelièvre, Joël / Ballell, Lluis / Selenski, Carolyn / Axtman, Matthew / Ghidelli-Disse, Sonja / Pflaumer, Hannah / Bösche, Markus / Drewes, Gerard / Freiberg, Gail M / Kurnick, Matthew D / Srikumaran, Myron / Kempf, Dale J / Green, Simon R / Ray, Peter C / Read, Kevin / Wyatt, Paul / Barry, Clifton E / Boshoff, Helena I

ACS infectious diseases

2016 Volume 3, Issue 1, Page(s) 18–33

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Antitubercular Agents/pharmacology ; Drug Design ; Drug Discovery ; Drug Resistance, Bacterial ; Gene Expression Regulation, Bacterial/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; IMP Dehydrogenase/antagonists & inhibitors ; Mice ; Mice, Inbred C57BL ; Molecular Structure ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Protein Conformation ; Rabbits ; Structure-Activity Relationship ; Sulfonamides/chemistry ; Sulfonamides/pharmacokinetics ; Sulfonamides/pharmacology ; Tuberculosis/drug therapy
Chemical Substances	Antitubercular Agents ; Sulfonamides ; IMP Dehydrogenase (EC 1.1.1.205)
Language	English
Publishing date	2016-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.6b00103
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Pharmacokinetic optimisation of novel indole-2-carboxamide cannabinoid CB₁ antagonists

Cowley, Phillip M. / Baker, James / Buchanan, Kirsteen I. / Carlyle, Ian / Clark, John K. / Clarkson, Thomas R. / Deehan, Maureen / Edwards, Darren / Kiyoi, Yasuko / Martin, Iain / Osbourn, Dawn / Walker, Glenn / Ward, Nick / Wishart, Grant

Bioorganic & medicinal chemistry letters

Volume v. 21,, Issue no. 7

Abstract	The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB₁ receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB₁ antagonist with high predicted human oral bioavailability.
Keywords	cannabinoids ; bioavailability ; receptors ; humans ; antagonists ; pharmacokinetics
Language	English
Document type	Article
ISSN	0960-894X
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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Article: discovery of novel indole-2-carboxamides as cannabinoid CB₁ receptor antagonists

Cowley, Phillip M. / Baker, James / Barn, David R. / Buchanan, Kirsteen I. / Carlyle, Ian / Clark, John K. / Clarkson, Thomas R. / Deehan, Maureen / Edwards, Darren / Goodwin, Richard R. / Jaap, David / Kiyoi, Yasuko / Mort, Chris / Palin, Ronald / Prosser, Alan / Walker, Glenn / Ward, Nick / Wishart, Grant / Young, Trevor

Bioorganic & medicinal chemistry letters

Volume v. 21,, Issue no. 1

Abstract	The discovery and structure–activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB₁ receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB₁ antagonist.
Keywords	cannabinoids ; structure-activity relationships ; receptors ; antagonists
Language	English
Document type	Article
ISSN	0960-894X
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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