Inhibitors of HIV-1 attachment: The discovery and structure-activity relationships of tetrahydroisoquinolines as replacements for the piperazine benzamide in the 3-glyoxylyl 6-azaindole pharmacophore.
Identifieur interne : 002B62 ( Ncbi/Checkpoint ); précédent : 002B61; suivant : 002B63Inhibitors of HIV-1 attachment: The discovery and structure-activity relationships of tetrahydroisoquinolines as replacements for the piperazine benzamide in the 3-glyoxylyl 6-azaindole pharmacophore.
Auteurs : Jacob J. Swidorski [États-Unis] ; Zheng Liu [États-Unis] ; Zhiwei Yin [États-Unis] ; Tao Wang [États-Unis] ; David J. Carini [États-Unis] ; Sandhya Rahematpura [États-Unis] ; Ming Zheng [États-Unis] ; Kim Johnson [États-Unis] ; Sharon Zhang [États-Unis] ; Pin-Fang Lin [États-Unis] ; Dawn D. Parker [États-Unis] ; Wenying Li [États-Unis] ; Nicholas A. Meanwell [États-Unis] ; Lawrence G. Hamann [États-Unis] ; Alicia Regueiro-Ren [États-Unis]Source :
- Bioorganic & medicinal chemistry letters [ 1464-3405 ] ; 2016.
Descripteurs français
- KwdFr :
- Attachement viral (), Benzamides (), Cellules HeLa, Composés aza (), Découverte de médicament, Humains, Indoles (), Infections à VIH (génétique), Infections à VIH (traitement médicamenteux), Inhibiteurs de fusion du VIH (), Inhibiteurs de fusion du VIH (pharmacologie), Inhibiteurs de fusion du VIH (synthèse chimique), Pipérazines (), Protéine d'enveloppe gp120 du VIH (antagonistes et inhibiteurs), Protéine d'enveloppe gp120 du VIH (génétique), Relation dose-effet des médicaments, Relation structure-activité, Réplication virale (), Structure moléculaire, Survie cellulaire (), Tétrahydroisoquinoléines (), Tétrahydroisoquinoléines (pharmacologie), Tétrahydroisoquinoléines (synthèse chimique), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- antagonistes et inhibiteurs : Protéine d'enveloppe gp120 du VIH.
- génétique : Infections à VIH, Protéine d'enveloppe gp120 du VIH.
- pharmacologie : Inhibiteurs de fusion du VIH, Tétrahydroisoquinoléines.
- synthèse chimique : Inhibiteurs de fusion du VIH, Tétrahydroisoquinoléines.
- traitement médicamenteux : Infections à VIH.
- Attachement viral, Benzamides, Cellules HeLa, Composés aza, Découverte de médicament, Humains, Indoles, Inhibiteurs de fusion du VIH, Pipérazines, Relation dose-effet des médicaments, Relation structure-activité, Réplication virale, Structure moléculaire, Survie cellulaire, Tétrahydroisoquinoléines, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Aza Compounds (chemistry), Benzamides (chemistry), Cell Survival (drug effects), Dose-Response Relationship, Drug, Drug Discovery, HIV Envelope Protein gp120 (antagonists & inhibitors), HIV Envelope Protein gp120 (genetics), HIV Fusion Inhibitors (chemical synthesis), HIV Fusion Inhibitors (chemistry), HIV Fusion Inhibitors (pharmacology), HIV Infections (drug therapy), HIV Infections (genetics), HIV-1 (drug effects), HeLa Cells, Humans, Indoles (chemistry), Molecular Structure, Piperazines (chemistry), Structure-Activity Relationship, Tetrahydroisoquinolines (chemical synthesis), Tetrahydroisoquinolines (chemistry), Tetrahydroisoquinolines (pharmacology), Virus Attachment (drug effects), Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : HIV Envelope Protein gp120.
- chemical , chemical synthesis : HIV Fusion Inhibitors, Tetrahydroisoquinolines.
- chemical , chemistry : Aza Compounds, Benzamides, HIV Fusion Inhibitors, Indoles, Piperazines, Tetrahydroisoquinolines.
- drug effects : Cell Survival, HIV-1, Virus Attachment, Virus Replication.
- drug therapy : HIV Infections.
- chemical , genetics : HIV Envelope Protein gp120, HIV Infections.
- chemical , pharmacology : HIV Fusion Inhibitors, Tetrahydroisoquinolines.
- Dose-Response Relationship, Drug, Drug Discovery, HeLa Cells, Humans, Molecular Structure, Structure-Activity Relationship.
Abstract
6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4-d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype viral infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein.
DOI: 10.1016/j.bmcl.2015.11.009
PubMed: 26584882
Affiliations:
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<author><name sortKey="Regueiro Ren, Alicia" sort="Regueiro Ren, Alicia" uniqKey="Regueiro Ren A" first="Alicia" last="Regueiro-Ren">Alicia Regueiro-Ren</name>
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<author><name sortKey="Yin, Zhiwei" sort="Yin, Zhiwei" uniqKey="Yin Z" first="Zhiwei" last="Yin">Zhiwei Yin</name>
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<author><name sortKey="Carini, David J" sort="Carini, David J" uniqKey="Carini D" first="David J" last="Carini">David J. Carini</name>
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<author><name sortKey="Rahematpura, Sandhya" sort="Rahematpura, Sandhya" uniqKey="Rahematpura S" first="Sandhya" last="Rahematpura">Sandhya Rahematpura</name>
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<author><name sortKey="Zheng, Ming" sort="Zheng, Ming" uniqKey="Zheng M" first="Ming" last="Zheng">Ming Zheng</name>
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<author><name sortKey="Johnson, Kim" sort="Johnson, Kim" uniqKey="Johnson K" first="Kim" last="Johnson">Kim Johnson</name>
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<author><name sortKey="Zhang, Sharon" sort="Zhang, Sharon" uniqKey="Zhang S" first="Sharon" last="Zhang">Sharon Zhang</name>
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<author><name sortKey="Lin, Pin Fang" sort="Lin, Pin Fang" uniqKey="Lin P" first="Pin-Fang" last="Lin">Pin-Fang Lin</name>
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<author><name sortKey="Parker, Dawn D" sort="Parker, Dawn D" uniqKey="Parker D" first="Dawn D" last="Parker">Dawn D. Parker</name>
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<author><name sortKey="Li, Wenying" sort="Li, Wenying" uniqKey="Li W" first="Wenying" last="Li">Wenying Li</name>
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<author><name sortKey="Meanwell, Nicholas A" sort="Meanwell, Nicholas A" uniqKey="Meanwell N" first="Nicholas A" last="Meanwell">Nicholas A. Meanwell</name>
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<author><name sortKey="Hamann, Lawrence G" sort="Hamann, Lawrence G" uniqKey="Hamann L" first="Lawrence G" last="Hamann">Lawrence G. Hamann</name>
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<author><name sortKey="Regueiro Ren, Alicia" sort="Regueiro Ren, Alicia" uniqKey="Regueiro Ren A" first="Alicia" last="Regueiro-Ren">Alicia Regueiro-Ren</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492</wicri:regionArea>
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</author>
</analytic>
<series><title level="j">Bioorganic & medicinal chemistry letters</title>
<idno type="eISSN">1464-3405</idno>
<imprint><date when="2016" type="published">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aza Compounds (chemistry)</term>
<term>Benzamides (chemistry)</term>
<term>Cell Survival (drug effects)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Drug Discovery</term>
<term>HIV Envelope Protein gp120 (antagonists & inhibitors)</term>
<term>HIV Envelope Protein gp120 (genetics)</term>
<term>HIV Fusion Inhibitors (chemical synthesis)</term>
<term>HIV Fusion Inhibitors (chemistry)</term>
<term>HIV Fusion Inhibitors (pharmacology)</term>
<term>HIV Infections (drug therapy)</term>
<term>HIV Infections (genetics)</term>
<term>HIV-1 (drug effects)</term>
<term>HeLa Cells</term>
<term>Humans</term>
<term>Indoles (chemistry)</term>
<term>Molecular Structure</term>
<term>Piperazines (chemistry)</term>
<term>Structure-Activity Relationship</term>
<term>Tetrahydroisoquinolines (chemical synthesis)</term>
<term>Tetrahydroisoquinolines (chemistry)</term>
<term>Tetrahydroisoquinolines (pharmacology)</term>
<term>Virus Attachment (drug effects)</term>
<term>Virus Replication (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Attachement viral ()</term>
<term>Benzamides ()</term>
<term>Cellules HeLa</term>
<term>Composés aza ()</term>
<term>Découverte de médicament</term>
<term>Humains</term>
<term>Indoles ()</term>
<term>Infections à VIH (génétique)</term>
<term>Infections à VIH (traitement médicamenteux)</term>
<term>Inhibiteurs de fusion du VIH ()</term>
<term>Inhibiteurs de fusion du VIH (pharmacologie)</term>
<term>Inhibiteurs de fusion du VIH (synthèse chimique)</term>
<term>Pipérazines ()</term>
<term>Protéine d'enveloppe gp120 du VIH (antagonistes et inhibiteurs)</term>
<term>Protéine d'enveloppe gp120 du VIH (génétique)</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Réplication virale ()</term>
<term>Structure moléculaire</term>
<term>Survie cellulaire ()</term>
<term>Tétrahydroisoquinoléines ()</term>
<term>Tétrahydroisoquinoléines (pharmacologie)</term>
<term>Tétrahydroisoquinoléines (synthèse chimique)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HIV Envelope Protein gp120</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>HIV Fusion Inhibitors</term>
<term>Tetrahydroisoquinolines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Aza Compounds</term>
<term>Benzamides</term>
<term>HIV Fusion Inhibitors</term>
<term>Indoles</term>
<term>Piperazines</term>
<term>Tetrahydroisoquinolines</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéine d'enveloppe gp120 du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Survival</term>
<term>HIV-1</term>
<term>Virus Attachment</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>HIV Infections</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>HIV Envelope Protein gp120</term>
<term>HIV Infections</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Infections à VIH</term>
<term>Protéine d'enveloppe gp120 du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de fusion du VIH</term>
<term>Tétrahydroisoquinoléines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>HIV Fusion Inhibitors</term>
<term>Tetrahydroisoquinolines</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Inhibiteurs de fusion du VIH</term>
<term>Tétrahydroisoquinoléines</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à VIH</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term>
<term>Drug Discovery</term>
<term>HeLa Cells</term>
<term>Humans</term>
<term>Molecular Structure</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Attachement viral</term>
<term>Benzamides</term>
<term>Cellules HeLa</term>
<term>Composés aza</term>
<term>Découverte de médicament</term>
<term>Humains</term>
<term>Indoles</term>
<term>Inhibiteurs de fusion du VIH</term>
<term>Pipérazines</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Réplication virale</term>
<term>Structure moléculaire</term>
<term>Survie cellulaire</term>
<term>Tétrahydroisoquinoléines</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4-d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype viral infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein. </div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Connecticut</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Connecticut"><name sortKey="Swidorski, Jacob J" sort="Swidorski, Jacob J" uniqKey="Swidorski J" first="Jacob J" last="Swidorski">Jacob J. Swidorski</name>
</region>
<name sortKey="Carini, David J" sort="Carini, David J" uniqKey="Carini D" first="David J" last="Carini">David J. Carini</name>
<name sortKey="Hamann, Lawrence G" sort="Hamann, Lawrence G" uniqKey="Hamann L" first="Lawrence G" last="Hamann">Lawrence G. Hamann</name>
<name sortKey="Johnson, Kim" sort="Johnson, Kim" uniqKey="Johnson K" first="Kim" last="Johnson">Kim Johnson</name>
<name sortKey="Li, Wenying" sort="Li, Wenying" uniqKey="Li W" first="Wenying" last="Li">Wenying Li</name>
<name sortKey="Lin, Pin Fang" sort="Lin, Pin Fang" uniqKey="Lin P" first="Pin-Fang" last="Lin">Pin-Fang Lin</name>
<name sortKey="Liu, Zheng" sort="Liu, Zheng" uniqKey="Liu Z" first="Zheng" last="Liu">Zheng Liu</name>
<name sortKey="Meanwell, Nicholas A" sort="Meanwell, Nicholas A" uniqKey="Meanwell N" first="Nicholas A" last="Meanwell">Nicholas A. Meanwell</name>
<name sortKey="Parker, Dawn D" sort="Parker, Dawn D" uniqKey="Parker D" first="Dawn D" last="Parker">Dawn D. Parker</name>
<name sortKey="Rahematpura, Sandhya" sort="Rahematpura, Sandhya" uniqKey="Rahematpura S" first="Sandhya" last="Rahematpura">Sandhya Rahematpura</name>
<name sortKey="Regueiro Ren, Alicia" sort="Regueiro Ren, Alicia" uniqKey="Regueiro Ren A" first="Alicia" last="Regueiro-Ren">Alicia Regueiro-Ren</name>
<name sortKey="Wang, Tao" sort="Wang, Tao" uniqKey="Wang T" first="Tao" last="Wang">Tao Wang</name>
<name sortKey="Yin, Zhiwei" sort="Yin, Zhiwei" uniqKey="Yin Z" first="Zhiwei" last="Yin">Zhiwei Yin</name>
<name sortKey="Zhang, Sharon" sort="Zhang, Sharon" uniqKey="Zhang S" first="Sharon" last="Zhang">Sharon Zhang</name>
<name sortKey="Zheng, Ming" sort="Zheng, Ming" uniqKey="Zheng M" first="Ming" last="Zheng">Ming Zheng</name>
</country>
</tree>
</affiliations>
</record>
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