Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 1; pp. 310 - 317
• Main Authors: Kesteleyn, Bart, Amssoms, Katie, Schepens, Wim, Hache, Geerwin, Verschueren, Wim, Van De Vreken, Wim, Rombauts, Klara, Meurs, Greet, Sterkens, Patrick, Stoops, Bart, Baert, Lieven, Austin, Nigel, Wegner, Jörg, Masungi, Chantal, Dierynck, Inge, Lundgren, Stina, Jönsson, Daniel, Parkes, Kevin, Kalayanov, Genadiy, Wallberg, Hans, Rosenquist, Åsa, Samuelsson, Bertil, Van Emelen, Kristof, Thuring, Jan Willem
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2013; Elsevier
• Subjects: Alkylation; Animals; binding sites; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacokinetics; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacokinetics; Drug Design; drugs; Half-Life; Halogenation; HIV Protease; HIV Protease - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacokinetics; HIV-1 - enzymology; HIV/AIDS; Human immunodeficiency virus 1; Humans; injection site; Life Sciences & Biomedicine; liver microsomes; Long-acting formulation; Microsomes, Liver - metabolism; Nanosuspension; Pharmacology & Pharmacy; Physical Sciences; Protease inhibitor; proteinase inhibitors; proteinases; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacokinetics; Rats; Science & Technology; Structure-Activity Relationship; HIV/AIDS; Long-acting formulation; Nanosuspension; Protease inhibitor; HIV Protease; POTENT; THERAPY; HYDROXYETHYLENE DIPEPTIDE ISOSTERES; ANALOGS; HUMAN-IMMUNODEFICIENCY-VIRUS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.10.095

The design and synthesis of novel HIV-1 protease inhibitors (PIs), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was directed towards the discovery of new PIs suitable for a long-acting injectable drug application for treating HIV/AIDS. The two most potent HIV-1 PIs 18 and 22, formulated as nanosuspensions, showed interesting compound release profiles over two months when injected intramuscularly in rats. 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 (R3) 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 (R1) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16–22) with EC50s on wild-type HIV-1 in the range of 0.8–1.8nM. 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.