title: Design and synthesis of HIV-1 protease inhibitors for a long-acting injectable drug application.
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.
authors.affiliation: Janssen Infectious Diseases, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium. bkestele@its.jnj.com
authors.forename: Bart
authors.initials: B
authors.lastname: Kesteleyn
authors.forename: Katie
authors.initials: K
authors.lastname: Amssoms
authors.forename: Wim
authors.initials: W
authors.lastname: Schepens
authors.forename: Geerwin
authors.initials: G
authors.lastname: Hache
authors.forename: Wim
authors.initials: W
authors.lastname: Verschueren
authors.forename: Wim
authors.initials: W
authors.lastname: Van De Vreken
authors.forename: Klara
authors.initials: K
authors.lastname: Rombauts
authors.forename: Greet
authors.initials: G
authors.lastname: Meurs
authors.forename: Patrick
authors.initials: P
authors.lastname: Sterkens
authors.forename: Bart
authors.initials: B
authors.lastname: Stoops
authors.forename: Lieven
authors.initials: L
authors.lastname: Baert
authors.forename: Nigel
authors.initials: N
authors.lastname: Austin
authors.forename: Jörg
authors.initials: J
authors.lastname: Wegner
authors.forename: Chantal
authors.initials: C
authors.lastname: Masungi
authors.forename: Inge
authors.initials: I
authors.lastname: Dierynck
authors.forename: Stina
authors.initials: S
authors.lastname: Lundgren
authors.forename: Daniel
authors.initials: D
authors.lastname: Jönsson
authors.forename: Kevin
authors.initials: K
authors.lastname: Parkes
authors.forename: Genadiy
authors.initials: G
authors.lastname: Kalayanov
authors.forename: Hans
authors.initials: H
authors.lastname: Wallberg
authors.forename: Asa
authors.initials: A
authors.lastname: Rosenquist
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Emelen
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Thuring
mesh_terms: D000478:Alkylation; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D015497:HIV-1 / Q000201:enzymology*; D006207:Half-Life; D054879:Halogenation; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D004151:Dipeptides; D017320:HIV Protease Inhibitors; D011725:Pyridines; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1