DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis
Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-11, Vol.64 (21), p.16159-16176 |
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| creator | Mowbray, Charles E Braillard, Stéphanie Glossop, Paul A Whitlock, Gavin A Jacobs, Robert T Speake, Jason Pandi, Bharathi Nare, Bakela Maes, Louis Yardley, Vanessa Freund, Yvonne Wall, Richard J Carvalho, Sandra Bello, Davide Van den Kerkhof, Magali Caljon, Guy Gilbert, Ian H Corpas-Lopez, Victoriano Lukac, Iva Patterson, Stephen Zuccotto, Fabio Wyllie, Susan |
| description | Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL. |
| doi_str_mv | 10.1021/acs.jmedchem.1c01437 |
| format | Article |
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Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c01437</identifier><identifier>PMID: 34711050</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antiprotozoal Agents - chemistry ; Antiprotozoal Agents - therapeutic use ; Benzoxazoles - chemistry ; Benzoxazoles - therapeutic use ; Boron Compounds - chemistry ; Boron Compounds - therapeutic use ; Cricetinae ; Disease Models, Animal ; Dogs ; Humans ; Leishmaniasis, Visceral - drug therapy ; Mice ; Pyridines - chemistry ; Pyridines - therapeutic use ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2021-11, Vol.64 (21), p.16159-16176</ispartof><rights>2021 The Authors. Published by American Chemical Society</rights><rights>2021 The Authors. Published by American Chemical Society 2021 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-ba5236d82c72b9958e986ddfdc48695ee072935c2841257fdf90b84da4fdce43</citedby><cites>FETCH-LOGICAL-a449t-ba5236d82c72b9958e986ddfdc48695ee072935c2841257fdf90b84da4fdce43</cites><orcidid>0000-0002-5238-1314 ; 0000-0001-8810-5605 ; 0000-0001-6567-5648 ; 0000-0003-3538-8116 ; 0000-0001-9669-2862 ; 0000-0002-3888-7423</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c01437$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01437$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34711050$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mowbray, Charles E</creatorcontrib><creatorcontrib>Braillard, Stéphanie</creatorcontrib><creatorcontrib>Glossop, Paul A</creatorcontrib><creatorcontrib>Whitlock, Gavin A</creatorcontrib><creatorcontrib>Jacobs, Robert T</creatorcontrib><creatorcontrib>Speake, Jason</creatorcontrib><creatorcontrib>Pandi, Bharathi</creatorcontrib><creatorcontrib>Nare, Bakela</creatorcontrib><creatorcontrib>Maes, Louis</creatorcontrib><creatorcontrib>Yardley, Vanessa</creatorcontrib><creatorcontrib>Freund, Yvonne</creatorcontrib><creatorcontrib>Wall, Richard J</creatorcontrib><creatorcontrib>Carvalho, Sandra</creatorcontrib><creatorcontrib>Bello, Davide</creatorcontrib><creatorcontrib>Van den Kerkhof, Magali</creatorcontrib><creatorcontrib>Caljon, Guy</creatorcontrib><creatorcontrib>Gilbert, Ian H</creatorcontrib><creatorcontrib>Corpas-Lopez, Victoriano</creatorcontrib><creatorcontrib>Lukac, Iva</creatorcontrib><creatorcontrib>Patterson, Stephen</creatorcontrib><creatorcontrib>Zuccotto, Fabio</creatorcontrib><creatorcontrib>Wyllie, Susan</creatorcontrib><title>DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.</description><subject>Animals</subject><subject>Antiprotozoal Agents - chemistry</subject><subject>Antiprotozoal Agents - therapeutic use</subject><subject>Benzoxazoles - chemistry</subject><subject>Benzoxazoles - therapeutic use</subject><subject>Boron Compounds - chemistry</subject><subject>Boron Compounds - therapeutic use</subject><subject>Cricetinae</subject><subject>Disease Models, Animal</subject><subject>Dogs</subject><subject>Humans</subject><subject>Leishmaniasis, Visceral - drug therapy</subject><subject>Mice</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - therapeutic use</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFv1DAQhS0EokvhHyDkI5csY8dObA5I7ZaWSqvCYcXVcuwJ6yqJi52tgF-Pl91WcOE0B3_vzfM8Ql4zWDLg7J11eXk7ondbHJfMARN1-4QsmORQCQXiKVkAcF7xhtcn5EXOtwBQM14_Jye1aBkDCQvSXdxcXFcNE-o9PaM38R4Heo7Tr_jDdjHFAemXhG4IU3B2oCs7-eDtjLSPic5bpJuEdh5xmmns6deQHabCrTHk7WinYHPIL8mz3g4ZXx3nKdlcftysPlXrz1fXq7N1ZYXQc9VZyevGK-5a3mktFWrVeN97J1SjJSK0XNfScSUYl23vew2dEt6KgqCoT8mHg-3drtufpWQqUcxdCqNNP020wfz7MoWt-RbvjZKaNaCKwdujQYrfd5hnM-7_Mwx2wrjLhksNoHXTsoKKA-pSzDlh_7iGgdm3Y0o75qEdc2ynyN78HfFR9FBHAeAA_JHHXZrKwf7v-RvyZZ-l</recordid><startdate>20211111</startdate><enddate>20211111</enddate><creator>Mowbray, Charles E</creator><creator>Braillard, Stéphanie</creator><creator>Glossop, Paul A</creator><creator>Whitlock, Gavin A</creator><creator>Jacobs, Robert T</creator><creator>Speake, Jason</creator><creator>Pandi, Bharathi</creator><creator>Nare, Bakela</creator><creator>Maes, Louis</creator><creator>Yardley, Vanessa</creator><creator>Freund, Yvonne</creator><creator>Wall, Richard J</creator><creator>Carvalho, Sandra</creator><creator>Bello, Davide</creator><creator>Van den Kerkhof, Magali</creator><creator>Caljon, Guy</creator><creator>Gilbert, Ian H</creator><creator>Corpas-Lopez, Victoriano</creator><creator>Lukac, Iva</creator><creator>Patterson, Stephen</creator><creator>Zuccotto, Fabio</creator><creator>Wyllie, Susan</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5238-1314</orcidid><orcidid>https://orcid.org/0000-0001-8810-5605</orcidid><orcidid>https://orcid.org/0000-0001-6567-5648</orcidid><orcidid>https://orcid.org/0000-0003-3538-8116</orcidid><orcidid>https://orcid.org/0000-0001-9669-2862</orcidid><orcidid>https://orcid.org/0000-0002-3888-7423</orcidid></search><sort><creationdate>20211111</creationdate><title>DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis</title><author>Mowbray, Charles E ; 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Med. Chem</addtitle><date>2021-11-11</date><risdate>2021</risdate><volume>64</volume><issue>21</issue><spage>16159</spage><epage>16176</epage><pages>16159-16176</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>34711050</pmid><doi>10.1021/acs.jmedchem.1c01437</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-5238-1314</orcidid><orcidid>https://orcid.org/0000-0001-8810-5605</orcidid><orcidid>https://orcid.org/0000-0001-6567-5648</orcidid><orcidid>https://orcid.org/0000-0003-3538-8116</orcidid><orcidid>https://orcid.org/0000-0001-9669-2862</orcidid><orcidid>https://orcid.org/0000-0002-3888-7423</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antiprotozoal Agents - chemistry Antiprotozoal Agents - therapeutic use Benzoxazoles - chemistry Benzoxazoles - therapeutic use Boron Compounds - chemistry Boron Compounds - therapeutic use Cricetinae Disease Models, Animal Dogs Humans Leishmaniasis, Visceral - drug therapy Mice Pyridines - chemistry Pyridines - therapeutic use Structure-Activity Relationship |
| title | DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis |
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