title: The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors.
abstract: Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.
authors: Essential Therapeutics, Inc., 850Maude Ave.,Mountain View, CA 94043, USA. wwatkins@etrx.com
authors: William J
authors: WJ
authors: Watkins
authors: Yakira
authors: Y
authors: Landaverry
authors: Roger
authors: R
authors: Léger
authors: Renée
authors: R
authors: Litman
authors: Thomas E
authors: TE
authors: Renau
authors: Nicole
authors: N
authors: Williams
authors: Rose
authors: R
authors: Yen
authors: Jason Z
authors: JZ
authors: Zhang
authors: Suzanne
authors: S
authors: Chamberland
authors: Deidre
authors: D
authors: Madsen
authors: David
authors: D
authors: Griffith
authors: Vrushali
authors: V
authors: Tembe
authors: Keith
authors: K
authors: Huie
authors: Michael N
authors: MN
authors: Dudley
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects*; D003959:Diamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007262:Infusions, Intravenous; D050356:Lipid Metabolism; D008297:Male; D008826:Microbial Sensitivity Tests; D015242:Ofloxacin / Q000378:metabolism / Q000494:pharmacology; D010949:Plasma / Q000187:drug effects*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000890:Anti-Infective Agents; D001425:Bacterial Outer Membrane Proteins; D003959:Diamines; D015242:Ofloxacin