SrasV1, Main, Exploration, bibRecord, 000C96

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/Exploration ); précédent : 000C95; suivant : 000C97

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).

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. Dicker

Source :

Journal of medicinal chemistry [ 1520-4804 ] ; 2018.

RBID : pubmed:30067361

Descripteurs français

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

Affiliations:

Le document en format XML

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<author><name sortKey="Samanta, Himadri" sort="Samanta, Himadri" uniqKey="Samanta H" first="Himadri" last="Samanta">Himadri Samanta</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>
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<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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<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>
</textClass>
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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>
</TEI>
<affiliations><list></list>
<tree><noCountry><name sortKey="Arora, Vinod" sort="Arora, Vinod" uniqKey="Arora V" first="Vinod" last="Arora">Vinod Arora</name>
<name sortKey="Beno, Brett R" sort="Beno, Brett R" uniqKey="Beno B" first="Brett R" last="Beno">Brett R. Beno</name>
<name sortKey="Chen, Jie" sort="Chen, Jie" uniqKey="Chen J" first="Jie" last="Chen">Jie Chen</name>
<name sortKey="Chen, Yan" sort="Chen, Yan" uniqKey="Chen Y" first="Yan" last="Chen">Yan Chen</name>
<name sortKey="Cockett, Mark I" sort="Cockett, Mark I" uniqKey="Cockett M" first="Mark I" last="Cockett">Mark I. Cockett</name>
<name sortKey="Dicker, Ira B" sort="Dicker, Ira B" uniqKey="Dicker I" first="Ira B" last="Dicker">Ira B. Dicker</name>
<name sortKey="Easter, John" sort="Easter, John" uniqKey="Easter J" first="John" last="Easter">John Easter</name>
<name sortKey="Hanumegowda, Umesh" sort="Hanumegowda, Umesh" uniqKey="Hanumegowda U" first="Umesh" last="Hanumegowda">Umesh Hanumegowda</name>
<name sortKey="Haskell, Roy" sort="Haskell, Roy" uniqKey="Haskell R" first="Roy" last="Haskell">Roy Haskell</name>
<name sortKey="Huang, Xiaohua S" sort="Huang, Xiaohua S" uniqKey="Huang X" first="Xiaohua S" last="Huang">Xiaohua S. Huang</name>
<name sortKey="Jenkins, Susan" sort="Jenkins, Susan" uniqKey="Jenkins S" first="Susan" last="Jenkins">Susan Jenkins</name>
<name sortKey="Krystal, Mark" sort="Krystal, Mark" uniqKey="Krystal M" first="Mark" last="Krystal">Mark Krystal</name>
<name sortKey="Li, Zhufang" sort="Li, Zhufang" uniqKey="Li Z" first="Zhufang" last="Li">Zhufang Li</name>
<name sortKey="Lin, Zeyu" sort="Lin, Zeyu" uniqKey="Lin Z" first="Zeyu" last="Lin">Zeyu 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="Nowicka Sans, Beata" sort="Nowicka Sans, Beata" uniqKey="Nowicka Sans B" first="Beata" last="Nowicka-Sans">Beata Nowicka-Sans</name>
<name sortKey="Parker, Dawn D" sort="Parker, Dawn D" uniqKey="Parker D" first="Dawn D" last="Parker">Dawn D. Parker</name>
<name sortKey="Protack, Tricia" sort="Protack, Tricia" uniqKey="Protack T" first="Tricia" last="Protack">Tricia Protack</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="Samanta, Himadri" sort="Samanta, Himadri" uniqKey="Samanta H" first="Himadri" last="Samanta">Himadri Samanta</name>
<name sortKey="Santone, Kenneth S" sort="Santone, Kenneth S" uniqKey="Santone K" first="Kenneth S" last="Santone">Kenneth S. Santone</name>
<name sortKey="Sin, Ny" sort="Sin, Ny" uniqKey="Sin N" first="Ny" last="Sin">Ny Sin</name>
<name sortKey="Sit, Sing Yuen" sort="Sit, Sing Yuen" uniqKey="Sit S" first="Sing-Yuen" last="Sit">Sing-Yuen Sit</name>
<name sortKey="Swidorski, Jacob J" sort="Swidorski, Jacob J" uniqKey="Swidorski J" first="Jacob J" last="Swidorski">Jacob J. Swidorski</name>
<name sortKey="Terry, Brian" sort="Terry, Brian" uniqKey="Terry B" first="Brian" last="Terry">Brian Terry</name>
<name sortKey="Venables, Brian L" sort="Venables, Brian L" uniqKey="Venables B" first="Brian L" last="Venables">Brian L. Venables</name>
<name sortKey="Zhang, Sharon" sort="Zhang, Sharon" uniqKey="Zhang S" first="Sharon" last="Zhang">Sharon Zhang</name>
<name sortKey="Zhu, Juliang" sort="Zhu, Juliang" uniqKey="Zhu J" first="Juliang" last="Zhu">Juliang Zhu</name>
</noCountry>
</tree>
</affiliations>
</record>

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Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Sante
   |area=    SrasV1
   |flux=    Main
   |étape=   Exploration
   |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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