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1.
J Med Chem ; 52(9): 2754-61, 2009 May 14.
Article in English | MEDLINE | ID: mdl-19374386

ABSTRACT

The medicinal chemistry and structure-activity relationships for a novel series of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV-integrase inhibitors are disclosed. Substituent effects were evaluated at the N-1, C-3, and 7-benzyl positions of the naphthyridinone ring system. Low nanomolar IC(50) values were achieved in an HIV-integrase strand transfer assay with both carboxylic ester and carboxamide groups at C-3. More importantly, several carboxamide congeners showed potent antiviral activity in cellular assays. A 7-benzyl substituent was found to be critical for potent enzyme inhibition, and an N-(2-methoxyethyl)carboxamide moiety at C-3 significantly reduced plasma protein binding effects in vitro. Pharmacokinetic data in rats for one carboxamide analogue demonstrated oral bioavailability and reasonable in vivo clearance.


Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV/enzymology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Carboxylic Acids/chemistry , Esters/chemistry , HIV/drug effects , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacokinetics , Male , Metabolic Clearance Rate , Naphthyridines/chemical synthesis , Naphthyridines/pharmacokinetics , Rats , Structure-Activity Relationship
2.
Drug Metab Dispos ; 32(7): 722-6, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15205387

ABSTRACT

GV196771 [E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-glydenemethyl)-1H-indole-2 carboxylic acid] is a potent antagonist of the modulatory glycine site of the N-methyl-d-aspartate receptor. GV196771 has low oral bioavailability (<10%) and plasma clearance ( approximately 2 ml/min/kg) in rats. P-Glycoprotein (Pgp) and breast cancer resistance protein (Bcrp) are ATP-binding cassette (ABC) transporters that limit the oral absorption of drugs and dietary constituents. The objective of this work was to assess the involvement of Pgp and/or Bcrp on the systemic exposure of GV196771 in mice. In vitro, GV196771 was a Bcrp substrate [basolateral-to-apical/apical-to-basolateral (B-->A/A-->B) ratio = 5.1] with high passive membrane permeability (P(app) = 64-170 nm/s); however, GV196771 was not an in vitro Mdr1a substrate (B-->A/A-->B ratio = 1.9; no effect of GF120918 on efflux ratio). The role of Pgp and Bcrp on the systemic exposure of GV196771 was assessed by pretreatment of wild-type and Pgp-deficient mdr1a/1b(-/-) mice with a single oral dose of GF120918 (50 mg/kg; a dual Pgp and Bcrp inhibitor) or vehicle (0.5% hydroxypropylmethylcellulose and 1% Tween 80) 2 h before administration of a single oral dose of GV196771 (2 mg/kg). Compared with wild-type animals, the GV196771 area under the plasma concentration-time curve [AUC((0-->6 h))] increased 6.2-fold in Pgp-deficient mice, 10.3-fold in GF120918-pretreated wild-type mice, and 16.4-fold in GF120918-pretreated Pgp-deficient mice. C(max) values changed in parallel with the AUC((0-->6 h)) values; however, t(max) remained relatively unchanged. This study supports a role for Pgp and Bcrp in attenuating the systemic exposure of GV196771 in mice and demonstrates that two ABC efflux transporters can have nonredundant roles in attenuating the disposition of a compound.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/metabolism , Indoles/pharmacokinetics , Pyrroles/pharmacokinetics , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/deficiency , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Acridines/pharmacology , Animals , Carbamates , Cell Line , Chromatography, Liquid , Furans , Male , Mass Spectrometry , Mice , Mice, Knockout , Receptors, N-Methyl-D-Aspartate/metabolism , Sulfonamides/pharmacology , Tetrahydroisoquinolines/pharmacology , Time Factors
3.
J Pharm Sci ; 92(10): 2082-9, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14502547

ABSTRACT

Recent in vitro studies have suggested that P-glycoprotein (Pgp) and passive membrane permeability may influence the brain concentrations of non-sedating (second-generation) antihistamines. The purpose of this study was to determine the importance of Pgp-mediated efflux on the in vivo brain distribution of the non-sedating antihistamine cetirizine (Zyrtec), and the structurally related sedating (first-generation) antihistamine hydroxyzine (Atarax). In vitro MDR1-MDCKII monolayer efflux assays demonstrated that cetirizine was a Pgp substrate (B-->A/A-->B + GF120918 ratio = 5.47) with low/moderate passive permeability (PappB-->A = 56.5 nm/s). In vivo, the cetirizine brain-to-free plasma concentration ratios (0.367 to 4.30) were 2.3- to 8.7-fold higher in Pgp-deficient mice compared with wild-type mice. In contrast, hydroxyzine was not a Pgp substrate in vitro (B-->A/A-->B ratio = 0.86), had high passive permeability (PappB-->A + GF120918 = 296 nm/s), and had brain-to-free plasma concentration ratios >73 in both Pgp-deficient and wild-type mice. These studies demonstrate that Pgp-mediated efflux and passive permeability contribute to the low cetirizine brain concentrations in mice and that these properties account for the differences in the sedation side-effect profiles of cetirizine and hydroxyzine.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Brain/metabolism , Cetirizine/pharmacokinetics , Histamine H1 Antagonists, Non-Sedating/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Animals , Area Under Curve , Cell Line , Cetirizine/blood , Chromatography, Liquid , Dogs , Histamine H1 Antagonists, Non-Sedating/blood , Humans , Hydroxyzine/blood , Hydroxyzine/pharmacokinetics , Injections, Intravenous , Male , Mass Spectrometry , Mice , Mice, Knockout , Permeability , Time Factors , Tissue Distribution
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