Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application
| Autor: | Kristof Van Emelen, Stina Lundgren, Lieven Baert, Jörg K. Wegner, Klara Rombauts, Wim Gaston Verschueren, Daniel Jönsson, Nigel Austin, Åsa Rosenquist, Kevin E. B. Parkes, Jan Willem Thuring, Patrick Sterkens, Wim Van De Vreken, Chantal Masungi, Inge Dierynck, Bart Kesteleyn, Hans Wallberg, Geerwin Hache, Katie Amssoms, Bertil Samuelsson, Bart Stoops, Wim Schepens, Genadiy Kalayanov, Greet Meurs |
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| Rok vydání: | 2012 |
| Předmět: |
Alkylation
Halogenation Stereochemistry Peptidomimetic Pyridines medicine.medical_treatment Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry Structure-Activity Relationship HIV-1 protease HIV Protease Drug Discovery medicine HIV Protease Inhibitor Moiety Structure–activity relationship Animals Humans Protease inhibitor (pharmacology) Molecular Biology Protease biology Chemistry Protease binding Organic Chemistry virus diseases Dipeptides HIV Protease Inhibitors Rats Drug Design biology.protein HIV-1 Microsomes Liver Molecular Medicine Carbamates Half-Life |
| Zdroj: | Bioorganicmedicinal chemistry letters. 23(1) |
| ISSN: | 1464-3405 |
| Popis: | The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1-22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe-Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R(3)) at the para-position of the P1' benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R(1)) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16-22) with EC(50)s on wild-type HIV-1 in the range of 0.8-1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS. |
| Databáze: | OpenAIRE |
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