Cassette dosing approach and quantitative structure-pharmacokinetic relationship study of antifungal N-myristoyltransferase inhibitors.
Pharmacokinetic (PK) parameters of N-myristoyltransferase (Nmt) inhibitors were measured, and a multivariate quantitative structure-pharmacokinetic relationship (QSPKR) model for predicting rat elimination half-life (t(1/2)) values was constructed. One hundred seven benzofuran derivatives have been selected as the data set for QSPKR analysis. The correlation between the t(1/2) values and 30 physicochemical descriptors was examined by a stepwise multiple linear regression method. The statistical analysis gives a significant QSPKR model (r = 0.843) with the following three variables: partial negative surface area (PNSA), atomic-based octanol/water partition coefficient (AlogP), and the number of rotational bonds (Rotlbonds). The QSPKR model obtained is predictive and simple, and would give a direction for designing new Nmt inhibitors having good PK profiles.
Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan. kiyoshi.hasegawa@roche.com
Kiyoshi
K
Hasegawa
Hidetoshi
H
Shindoh
Yasuhiko
Y
Shiratori
Tatsuo
T
Ohtsuka
Yuko
Y
Aoki
Shigeyasu
S
Ichihara
Ikuo
I
Horii
Nobuo
N
Shimma
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D001572:Benzofurans / Q000737:chemistry / Q000493:pharmacokinetics; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D008956:Models, Chemical; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011916:Rats, Inbred F344
D000935:Antifungal Agents; D001572:Benzofurans; D004791:Enzyme Inhibitors; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase