Sökning: id:"swepub:oai:DiVA.org:uu-135157" > Hiv-1 Protease Inhi...
Fältnamn | Indikatorer | Metadata |
---|---|---|
000 | 03457naa a2200445 4500 | |
001 | oai:DiVA.org:uu-135157 | |
003 | SwePub | |
008 | 101206s2011 | |||||||||||000 ||eng| | |
024 | 7 | a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1351572 URI |
024 | 7 | a https://doi.org/10.1039/c1md00077b2 DOI |
040 | a (SwePub)uu | |
041 | a engb eng | |
042 | 9 SwePub | |
072 | 7 | a ref2 swepub-contenttype |
072 | 7 | a art2 swepub-publicationtype |
100 | 1 | a Öhrngren, Peru Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 aut0 (Swepub:uu)peohr049 |
245 | 1 0 | a Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents |
264 | 1 | b Royal Society of Chemistry (RSC),c 2011 |
338 | a print2 rdacarrier | |
520 | a 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. | |
650 | 7 | a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Läkemedelskemi0 (SwePub)301032 hsv//swe |
650 | 7 | a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medicinal Chemistry0 (SwePub)301032 hsv//eng |
653 | a HIV | |
653 | a protease | |
653 | a inhibitor | |
653 | a Medicinal Chemistry | |
653 | a Läkemedelskemi | |
700 | 1 | a Wu, Xiongyuu Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 aut |
700 | 1 | a Persson, Magnusu Uppsala universitet,Struktur- och molekylärbiologi4 aut0 (Swepub:uu)majoh169 |
700 | 1 | a Ekegren, Jenny4 aut |
700 | 1 | a Wallberg, Hansu Medivir AB4 aut |
700 | 1 | a Vrang, Lotta4 aut |
700 | 1 | a Rosenquist, Åsau Medivir AB4 aut |
700 | 1 | a Samuelsson, Bertilu Medivir AB4 aut |
700 | 1 | a Unge, Torstenu Uppsala universitet,Struktur- och molekylärbiologi4 aut0 (Swepub:uu)torsunge |
700 | 1 | a Larhed, Matsu Uppsala universitet,Avdelningen för organisk farmaceutisk kemi4 aut0 (Swepub:uu)matslarh |
710 | 2 | a Uppsala universitetb Avdelningen för organisk farmaceutisk kemi4 org |
773 | 0 | t MedChemCommd : Royal Society of Chemistry (RSC)g 2:8, s. 701-709q 2:8<701-709x 2040-2503x 2040-2511 |
856 | 4 8 | u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-135157 |
856 | 4 8 | u https://doi.org/10.1039/c1md00077b |
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