2. Academic Validation
  3. Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application

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

  • Bioorg Med Chem Lett. 2013 Jan 1;23(1):310-7. doi: 10.1016/j.bmcl.2012.10.095.
Bart Kesteleyn 1,  Katie Amssoms,  Wim Schepens,  Geerwin Hache,  Wim Verschueren,  Wim Van De Vreken,  Klara Rombauts,  Greet Meurs,  Patrick Sterkens,  Bart Stoops,  Lieven Baert,  Nigel Austin,  Jörg Wegner,  Chantal Masungi,  Inge Dierynck,  Stina Lundgren,  Daniel Jönsson,  Kevin Parkes,  Genadiy Kalayanov,  Hans Wallberg,  Asa Rosenquist,  Bertil Samuelsson,  Kristof Van Emelen,  Jan Willem Thuring
Affiliations

Affiliation

  • 1 Janssen Infectious Diseases, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium. bkestele@its.jnj.com
PMID: 23177258 DOI: 10.1016/j.bmcl.2012.10.095
Abstract

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.

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