Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents

Öhrngren, PerUppsala universitet,Avdelningen för organisk farmaceutisk kemi (author)

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.

Wu, XiongyuUppsala universitet,Avdelningen för organisk farmaceutisk kemi (author)
Persson, MagnusUppsala universitet,Struktur- och molekylärbiologi(Swepub:uu)majoh169 (author)
Ekegren, Jenny (author)
Wallberg, HansMedivir AB (author)
Vrang, Lotta (author)
Rosenquist, ÅsaMedivir AB (author)
Samuelsson, BertilMedivir AB (author)
Unge, TorstenUppsala universitet,Struktur- och molekylärbiologi(Swepub:uu)torsunge (author)
Larhed, MatsUppsala universitet,Avdelningen för organisk farmaceutisk kemi(Swepub:uu)matslarh (author)
Uppsala universitetAvdelningen för organisk farmaceutisk kemi (creator_code:org_t)

In:MedChemComm: Royal Society of Chemistry (RSC)2:8, s. 701-7092040-25032040-2511

By the author/editor: Öhrngren, Per; Wu, Xiongyu; Persson, Magnus; Ekegren, Jenny; Wallberg, Hans; Vrang, Lotta; show more...; Rosenquist, Åsa; Samuelsson, Bert ...; Unge, Torsten; Larhed, Mats; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medicinal Chemis ...

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.