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Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents
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- Öhrngren, Per (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Wu, Xiongyu (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Persson, Magnus (author)
- Uppsala universitet,Struktur- och molekylärbiologi
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- Ekegren, Jenny (author)
- Vrang, Lotta (author)
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- (creator_code:org_t)
- Royal Society of Chemistry (RSC), 2011
- 2011
- English.
- In: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 2:8, s. 701-709
- Journal article (peer-reviewed)
Abstract
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- Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as thetransition-state mimic have been synthesised and evaluated. Replacement of the previously used, butmetabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moietiesprovided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 mM, respectively). The P10subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing thecorresponding inhibitors with retained activity. Permeability and stability studies showed examples inthe same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes(9a and 9d) supplied detailed structural information. The binding modes were compared tothose of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novelinhibitors with an elongated P1' side chain enabled a previously unexploited edge-on interaction withPhe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the proteaseactive site.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- HIV
- protease
- inhibitor
- Medicinal Chemistry
- Läkemedelskemi
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- ref (subject category)
- art (subject category)
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- Öhrngren, Per
- Wu, Xiongyu
- Persson, Magnus
- Ekegren, Jenny
- Wallberg, Hans
- Vrang, Lotta
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- Rosenquist, Åsa
- Samuelsson, Bert ...
- Unge, Torsten
- Larhed, Mats
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- MEDICAL AND HEALTH SCIENCES
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- MedChemComm
- By the university
- Uppsala University
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