The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors.
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.
Watkins
William J
WJ
Essential Therapeutics, Inc., 850Maude Ave.,Mountain View, CA 94043, USA. wwatkins@etrx.com
Landaverry
Yakira
Y
Léger
Roger
R
Litman
Renée
R
Renau
Thomas E
TE
Williams
Nicole
N
Yen
Rose
R
Zhang
Jason Z
JZ
Chamberland
Suzanne
S
Madsen
Deidre
D
Griffith
David
D
Tembe
Vrushali
V
Huie
Keith
K
Dudley
Michael N
MN
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
D000890:Anti-Infective Agents; D001425:Bacterial Outer Membrane Proteins; D003959:Diamines; D015242:Ofloxacin