Drug metabolism and pharmacokinetics of 4-substituted methoxybenzoyl-aryl-thiazoles.
Tubulins are some of the oldest and most extensively studied therapeutic targets for cancer. Although many tubulin polymerizing and depolymerizing agents are known, the search for improved agents continues. We screened a class of tubulins targeting small molecules and identified 4-(3,4,5-trimethoxybenzoyl)-2-phenyl-thiazole (SMART-H) as our lead compound. SMART-H inhibited the proliferation of a variety of cancer cells in vitro, at subnanomolar IC(50), and in vivo, in nude mice xenografts, with near 100% tumor growth inhibition. Metabolic stability studies with SMART-H in liver microsomes of four species (mouse, rat, dog, and human) revealed half-lives between <5 and 30 min, demonstrating an interspecies variability. The clearance predicted based on in vitro data correlated well with in vivo clearance obtained from mouse, rat, and dog in vivo pharmacokinetic studies. SMART-H underwent four major metabolic processes, including ketone reduction, demethylation, combination of ketone reduction and demethylation, and hydroxylation in human liver microsomes. Metabolite identification studies revealed that the ketone and the methoxy groups of SMART-H were most labile and that ketone reduction was the dominant metabolism reaction in human liver microsomes. We designed and tested four derivatives of SMART-H to improve the metabolic stability. The oxime and hydrazide derivatives, replacing the ketone site, demonstrated a 2- to 3-fold improved half-life in human liver microsomes, indicating that our prediction regarding metabolic stability of SMART-H can be extended by blocking ketone reduction. These studies led us to the next generation of SMART compounds with greater metabolic stability and higher pharmacologic potency.
Li
Chien-Ming
CM
GTx Inc, Memphis, Tennessee, USA.
Lu
Yan
Y
Narayanan
Ramesh
R
Miller
Duane D
DD
Dalton
James T
JT
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism*; D011237:Predictive Value of Tests; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D013045:Species Specificity; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
C556409:4-(3,4,5-trimethoxybenzoyl)-2-phenylthiazole; D054852:Small Molecule Libraries; D013844:Thiazoles; D014230:Triazoles; D050257:Tubulin Modulators