Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. V: 4-Substituted and 2,4-disubstituted analogs of nevirapine
Identifieur interne : 000991 ( PascalFrancis/Curation ); précédent : 000990; suivant : 000992Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. V: 4-Substituted and 2,4-disubstituted analogs of nevirapine
Auteurs : T. A. Kelly [États-Unis] ; J. R. Proudfoot ; D. W. Mcneil ; U. R. Patel ; E. David ; K. D. Hargrave ; P. M. Grob ; M. Cardozo ; A. Agarwal ; J. AdamsSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 1995.
Descripteurs français
- Pascal (Inist)
- Relation structure activité, Antiviral, Inhibiteur enzyme, RNA-directed DNA polymerase, Névirapine, Résistance, Synthèse chimique, Hétérocycle azote, Composé tricyclique, Lactame, Dipyrido[3,2-b:2',3'-e][1,4]diazépin-6-one(4-[(4-aminophénoxy)méthyl]-11-cyclopropyl-5,6-dihydro), Dipyrido[3,2-b:2',3'-e][1,4]diazépin-6-one(11-cyclopropyl-5,6-dihydro-4-[(4-éthylaminophénoxy)méthyl]), Dipyridodiazépinone, Dipyridodiazépine dérivé, Composé non nucléoside.
English descriptors
- KwdEn :
Abstract
Molecular modeling analysis of the recently published X-ray crystal structure of nevirapine bound to wild type human immunodeficiency virus type 1 reverse transcriptase (WT-RT) indicated the presence of a lipophilic cavity proximal to the 4-position of the inhibitor. A series of 4-substituted derivatives of nevirapine were thus synthesized to assess structure-activity relationships (SARs) and to see if increased binding to this region might translate into greater activity against mutant RTs. The results show that compounds with an appropriately spaced aryl ring appended to the 4-position of the dipyridodiazepinone ring system show good activity against WT-RT. Furthermore certain derivatives appear to inhibit the Y181C mutant RT. Attempts to combine these results with the recent discovery that 2-substituents enhance activity against the Y181C mutant led to a few compounds with moderate activity against both enzymes. The SAR of these two positions, however, could not be combined in a simple fashion.
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Pascal:96-0038342Le document en format XML
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<author><name sortKey="Hargrave, K D" sort="Hargrave, K D" uniqKey="Hargrave K" first="K. D." last="Hargrave">K. D. Hargrave</name>
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<author><name sortKey="Grob, P M" sort="Grob, P M" uniqKey="Grob P" first="P. M." last="Grob">P. M. Grob</name>
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<author><name sortKey="Agarwal, A" sort="Agarwal, A" uniqKey="Agarwal A" first="A." last="Agarwal">A. Agarwal</name>
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<term>Chemical synthesis</term>
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<term>Lactam</term>
<term>Nitrogen heterocycle</term>
<term>Nonnucleoside compound</term>
<term>RNA-directed DNA polymerase</term>
<term>Resistance</term>
<term>Structure activity relation</term>
<term>Tricyclic compound</term>
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<keywords scheme="Pascal" xml:lang="fr"><term>Relation structure activité</term>
<term>Antiviral</term>
<term>Inhibiteur enzyme</term>
<term>RNA-directed DNA polymerase</term>
<term>Névirapine</term>
<term>Résistance</term>
<term>Synthèse chimique</term>
<term>Hétérocycle azote</term>
<term>Composé tricyclique</term>
<term>Lactame</term>
<term>Dipyrido[3,2-b:2',3'-e][1,4]diazépin-6-one(4-[(4-aminophénoxy)méthyl]-11-cyclopropyl-5,6-dihydro)</term>
<term>Dipyrido[3,2-b:2',3'-e][1,4]diazépin-6-one(11-cyclopropyl-5,6-dihydro-4-[(4-éthylaminophénoxy)méthyl])</term>
<term>Dipyridodiazépinone</term>
<term>Dipyridodiazépine dérivé</term>
<term>Composé non nucléoside</term>
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<front><div type="abstract" xml:lang="en">Molecular modeling analysis of the recently published X-ray crystal structure of nevirapine bound to wild type human immunodeficiency virus type 1 reverse transcriptase (WT-RT) indicated the presence of a lipophilic cavity proximal to the 4-position of the inhibitor. A series of 4-substituted derivatives of nevirapine were thus synthesized to assess structure-activity relationships (SARs) and to see if increased binding to this region might translate into greater activity against mutant RTs. The results show that compounds with an appropriately spaced aryl ring appended to the 4-position of the dipyridodiazepinone ring system show good activity against WT-RT. Furthermore certain derivatives appear to inhibit the Y181C mutant RT. Attempts to combine these results with the recent discovery that 2-substituents enhance activity against the Y181C mutant led to a few compounds with moderate activity against both enzymes. The SAR of these two positions, however, could not be combined in a simple fashion.</div>
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<fC01 i1="01" l="ENG"><s0>Molecular modeling analysis of the recently published X-ray crystal structure of nevirapine bound to wild type human immunodeficiency virus type 1 reverse transcriptase (WT-RT) indicated the presence of a lipophilic cavity proximal to the 4-position of the inhibitor. A series of 4-substituted derivatives of nevirapine were thus synthesized to assess structure-activity relationships (SARs) and to see if increased binding to this region might translate into greater activity against mutant RTs. The results show that compounds with an appropriately spaced aryl ring appended to the 4-position of the dipyridodiazepinone ring system show good activity against WT-RT. Furthermore certain derivatives appear to inhibit the Y181C mutant RT. Attempts to combine these results with the recent discovery that 2-substituents enhance activity against the Y181C mutant led to a few compounds with moderate activity against both enzymes. The SAR of these two positions, however, could not be combined in a simple fashion.</s0>
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<s5>01</s5>
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<s5>03</s5>
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<s5>03</s5>
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<s5>03</s5>
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<s5>04</s5>
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<s5>04</s5>
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<fC03 i1="04" i2="X" l="SPA"><s0>RNA-directed DNA polymerase</s0>
<s2>FE</s2>
<s5>04</s5>
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<s2>NK</s2>
<s2>FR</s2>
<s5>05</s5>
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<s5>06</s5>
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<s5>06</s5>
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<s5>10</s5>
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<s2>NK</s2>
<s2>FR</s2>
<s4>INC</s4>
<s5>62</s5>
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<fC03 i1="12" i2="X" l="FRE"><s0>Dipyrido[3,2-b:2',3'-e][1,4]diazépin-6-one(11-cyclopropyl-5,6-dihydro-4-[(4-éthylaminophénoxy)méthyl])</s0>
<s2>NK</s2>
<s2>FR</s2>
<s4>INC</s4>
<s5>63</s5>
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<s5>64</s5>
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<fC03 i1="14" i2="X" l="FRE"><s0>Dipyridodiazépine dérivé</s0>
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<s5>96</s5>
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<s2>FE</s2>
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<fC07 i1="02" i2="X" l="ENG"><s0>Transferases</s0>
<s2>FE</s2>
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<s2>FE</s2>
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<fN21><s1>015</s1>
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