Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Identifieur interne : 000C96 ( Main/Curation ); précédent : 000C95; suivant : 000C97Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
Auteurs : Alicia Regueiro-Ren ; Jacob J. Swidorski ; Zheng Liu ; Yan Chen ; Ny Sin ; Sing-Yuen Sit ; Jie Chen ; Brian L. Venables ; Juliang Zhu ; Beata Nowicka-Sans ; Tricia Protack ; Zeyu Lin ; Brian Terry ; Himadri Samanta ; Sharon Zhang ; Zhufang Li ; John Easter ; Brett R. Beno ; Vinod Arora ; Xiaohua S. Huang ; Sandhya Rahematpura ; Dawn D. Parker ; Roy Haskell ; Kenneth S. Santone ; Mark I. Cockett ; Mark Krystal ; Nicholas A. Meanwell ; Susan Jenkins ; Umesh Hanumegowda ; Ira B. DickerSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2018.
Descripteurs français
- KwdFr :
- Acide benzoïque (), Administration par voie orale, Agents antiVIH (), Agents antiVIH (pharmacocinétique), Agents antiVIH (pharmacologie), Animaux, Biodisponibilité, Chiens, Chrysènes (), Chrysènes (pharmacologie), Conception de médicament, Humains, Lignées consanguines de souris, Macaca fascicularis, Microsomes du foie (), Morpholines (), Morpholines (pharmacologie), Mâle, Polymorphisme génétique, Rat Sprague-Dawley, Relation structure-activité, Souris knockout, Stabilité de médicament, Techniques de chimie synthétique, Triterpènes (), Triterpènes (pharmacologie), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (génétique).
- MESH :
- génétique : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- pharmacocinétique : Agents antiVIH.
- pharmacologie : Agents antiVIH, Chrysènes, Morpholines, Triterpènes.
- Acide benzoïque, Administration par voie orale, Agents antiVIH, Animaux, Biodisponibilité, Chiens, Chrysènes, Conception de médicament, Humains, Lignées consanguines de souris, Macaca fascicularis, Microsomes du foie, Morpholines, Mâle, Polymorphisme génétique, Rat Sprague-Dawley, Relation structure-activité, Souris knockout, Stabilité de médicament, Techniques de chimie synthétique, Triterpènes, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics), Administration, Oral, Animals, Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacokinetics), Anti-HIV Agents (pharmacology), Benzoic Acid (chemistry), Biological Availability, Chemistry Techniques, Synthetic, Chrysenes (chemistry), Chrysenes (pharmacology), Dogs, Drug Design, Drug Stability, HIV-1 (drug effects), HIV-1 (genetics), Humans, Macaca fascicularis, Male, Mice, Inbred Strains, Mice, Knockout, Microsomes, Liver (drug effects), Morpholines (chemistry), Morpholines (pharmacology), Polymorphism, Genetic, Rats, Sprague-Dawley, Structure-Activity Relationship, Triterpenes (chemistry), Triterpenes (pharmacology).
- MESH :
- chemical , chemistry : Anti-HIV Agents, Benzoic Acid, Chrysenes, Morpholines, Triterpenes.
- chemical , genetics : ATP Binding Cassette Transporter, Subfamily B, Member 1.
- chemical , pharmacokinetics : Anti-HIV Agents.
- chemical , pharmacology : Anti-HIV Agents, Chrysenes, Morpholines, Triterpenes.
- drug effects : HIV-1, Microsomes, Liver.
- genetics : HIV-1.
- Administration, Oral, Animals, Biological Availability, Chemistry Techniques, Synthetic, Dogs, Drug Design, Drug Stability, Humans, Macaca fascicularis, Male, Mice, Inbred Strains, Mice, Knockout, Polymorphism, Genetic, Rats, Sprague-Dawley, Structure-Activity Relationship.
Abstract
GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
DOI: 10.1021/acs.jmedchem.8b00854
PubMed: 30067361
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pubmed:30067361Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).</title>
<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="Swidorski, Jacob J" sort="Swidorski, Jacob J" uniqKey="Swidorski J" first="Jacob J" last="Swidorski">Jacob J. Swidorski</name>
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<author><name sortKey="Liu, Zheng" sort="Liu, Zheng" uniqKey="Liu Z" first="Zheng" last="Liu">Zheng Liu</name>
</author>
<author><name sortKey="Chen, Yan" sort="Chen, Yan" uniqKey="Chen Y" first="Yan" last="Chen">Yan Chen</name>
</author>
<author><name sortKey="Sin, Ny" sort="Sin, Ny" uniqKey="Sin N" first="Ny" last="Sin">Ny Sin</name>
</author>
<author><name sortKey="Sit, Sing Yuen" sort="Sit, Sing Yuen" uniqKey="Sit S" first="Sing-Yuen" last="Sit">Sing-Yuen Sit</name>
</author>
<author><name sortKey="Chen, Jie" sort="Chen, Jie" uniqKey="Chen J" first="Jie" last="Chen">Jie Chen</name>
</author>
<author><name sortKey="Venables, Brian L" sort="Venables, Brian L" uniqKey="Venables B" first="Brian L" last="Venables">Brian L. Venables</name>
</author>
<author><name sortKey="Zhu, Juliang" sort="Zhu, Juliang" uniqKey="Zhu J" first="Juliang" last="Zhu">Juliang Zhu</name>
</author>
<author><name sortKey="Nowicka Sans, Beata" sort="Nowicka Sans, Beata" uniqKey="Nowicka Sans B" first="Beata" last="Nowicka-Sans">Beata Nowicka-Sans</name>
</author>
<author><name sortKey="Protack, Tricia" sort="Protack, Tricia" uniqKey="Protack T" first="Tricia" last="Protack">Tricia Protack</name>
</author>
<author><name sortKey="Lin, Zeyu" sort="Lin, Zeyu" uniqKey="Lin Z" first="Zeyu" last="Lin">Zeyu Lin</name>
</author>
<author><name sortKey="Terry, Brian" sort="Terry, Brian" uniqKey="Terry B" first="Brian" last="Terry">Brian Terry</name>
</author>
<author><name sortKey="Samanta, Himadri" sort="Samanta, Himadri" uniqKey="Samanta H" first="Himadri" last="Samanta">Himadri Samanta</name>
</author>
<author><name sortKey="Zhang, Sharon" sort="Zhang, Sharon" uniqKey="Zhang S" first="Sharon" last="Zhang">Sharon Zhang</name>
</author>
<author><name sortKey="Li, Zhufang" sort="Li, Zhufang" uniqKey="Li Z" first="Zhufang" last="Li">Zhufang Li</name>
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<author><name sortKey="Easter, John" sort="Easter, John" uniqKey="Easter J" first="John" last="Easter">John Easter</name>
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<author><name sortKey="Beno, Brett R" sort="Beno, Brett R" uniqKey="Beno B" first="Brett R" last="Beno">Brett R. Beno</name>
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<author><name sortKey="Arora, Vinod" sort="Arora, Vinod" uniqKey="Arora V" first="Vinod" last="Arora">Vinod Arora</name>
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<author><name sortKey="Huang, Xiaohua S" sort="Huang, Xiaohua S" uniqKey="Huang X" first="Xiaohua S" last="Huang">Xiaohua S. Huang</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="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="Haskell, Roy" sort="Haskell, Roy" uniqKey="Haskell R" first="Roy" last="Haskell">Roy Haskell</name>
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<author><name sortKey="Santone, Kenneth S" sort="Santone, Kenneth S" uniqKey="Santone K" first="Kenneth S" last="Santone">Kenneth S. Santone</name>
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<author><name sortKey="Cockett, Mark I" sort="Cockett, Mark I" uniqKey="Cockett M" first="Mark I" last="Cockett">Mark I. Cockett</name>
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<author><name sortKey="Krystal, Mark" sort="Krystal, Mark" uniqKey="Krystal M" first="Mark" last="Krystal">Mark Krystal</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="Jenkins, Susan" sort="Jenkins, Susan" uniqKey="Jenkins S" first="Susan" last="Jenkins">Susan Jenkins</name>
</author>
<author><name sortKey="Hanumegowda, Umesh" sort="Hanumegowda, Umesh" uniqKey="Hanumegowda U" first="Umesh" last="Hanumegowda">Umesh Hanumegowda</name>
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<author><name sortKey="Dicker, Ira B" sort="Dicker, Ira B" uniqKey="Dicker I" first="Ira B" last="Dicker">Ira B. Dicker</name>
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<series><title level="j">Journal of medicinal chemistry</title>
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<imprint><date when="2018" type="published">2018</date>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)</term>
<term>Administration, Oral</term>
<term>Animals</term>
<term>Anti-HIV Agents (chemistry)</term>
<term>Anti-HIV Agents (pharmacokinetics)</term>
<term>Anti-HIV Agents (pharmacology)</term>
<term>Benzoic Acid (chemistry)</term>
<term>Biological Availability</term>
<term>Chemistry Techniques, Synthetic</term>
<term>Chrysenes (chemistry)</term>
<term>Chrysenes (pharmacology)</term>
<term>Dogs</term>
<term>Drug Design</term>
<term>Drug Stability</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-1 (genetics)</term>
<term>Humans</term>
<term>Macaca fascicularis</term>
<term>Male</term>
<term>Mice, Inbred Strains</term>
<term>Mice, Knockout</term>
<term>Microsomes, Liver (drug effects)</term>
<term>Morpholines (chemistry)</term>
<term>Morpholines (pharmacology)</term>
<term>Polymorphism, Genetic</term>
<term>Rats, Sprague-Dawley</term>
<term>Structure-Activity Relationship</term>
<term>Triterpenes (chemistry)</term>
<term>Triterpenes (pharmacology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Acide benzoïque ()</term>
<term>Administration par voie orale</term>
<term>Agents antiVIH ()</term>
<term>Agents antiVIH (pharmacocinétique)</term>
<term>Agents antiVIH (pharmacologie)</term>
<term>Animaux</term>
<term>Biodisponibilité</term>
<term>Chiens</term>
<term>Chrysènes ()</term>
<term>Chrysènes (pharmacologie)</term>
<term>Conception de médicament</term>
<term>Humains</term>
<term>Lignées consanguines de souris</term>
<term>Macaca fascicularis</term>
<term>Microsomes du foie ()</term>
<term>Morpholines ()</term>
<term>Morpholines (pharmacologie)</term>
<term>Mâle</term>
<term>Polymorphisme génétique</term>
<term>Rat Sprague-Dawley</term>
<term>Relation structure-activité</term>
<term>Souris knockout</term>
<term>Stabilité de médicament</term>
<term>Techniques de chimie synthétique</term>
<term>Triterpènes ()</term>
<term>Triterpènes (pharmacologie)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Benzoic Acid</term>
<term>Chrysenes</term>
<term>Morpholines</term>
<term>Triterpenes</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>ATP Binding Cassette Transporter, Subfamily B, Member 1</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Anti-HIV Agents</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Chrysenes</term>
<term>Morpholines</term>
<term>Triterpenes</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term>
<term>Microsomes, Liver</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Agents antiVIH</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term>
<term>Chrysènes</term>
<term>Morpholines</term>
<term>Triterpènes</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Administration, Oral</term>
<term>Animals</term>
<term>Biological Availability</term>
<term>Chemistry Techniques, Synthetic</term>
<term>Dogs</term>
<term>Drug Design</term>
<term>Drug Stability</term>
<term>Humans</term>
<term>Macaca fascicularis</term>
<term>Male</term>
<term>Mice, Inbred Strains</term>
<term>Mice, Knockout</term>
<term>Polymorphism, Genetic</term>
<term>Rats, Sprague-Dawley</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Acide benzoïque</term>
<term>Administration par voie orale</term>
<term>Agents antiVIH</term>
<term>Animaux</term>
<term>Biodisponibilité</term>
<term>Chiens</term>
<term>Chrysènes</term>
<term>Conception de médicament</term>
<term>Humains</term>
<term>Lignées consanguines de souris</term>
<term>Macaca fascicularis</term>
<term>Microsomes du foie</term>
<term>Morpholines</term>
<term>Mâle</term>
<term>Polymorphisme génétique</term>
<term>Rat Sprague-Dawley</term>
<term>Relation structure-activité</term>
<term>Souris knockout</term>
<term>Stabilité de médicament</term>
<term>Techniques de chimie synthétique</term>
<term>Triterpènes</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
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<front><div type="abstract" xml:lang="en">GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC<sub>50</sub>
<15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.</div>
</front>
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{{Explor lien |wiki= Sante |area= SrasV1 |flux= Main |étape= Curation |type= RBID |clé= pubmed:30067361 |texte= Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176). }}
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