ABSTRACT
3,5-diaryl-4,5-dihydropyrazoles were discovered to be potent KSP inhibitors with excellent in vivo potency. These enzyme inhibitors possess desirable physical properties that can be readily modified by incorporation of a weakly basic amine. Careful adjustment of amine basicity was essential for preserving cellular potency in a multidrug resistant cell line while maintaining good aqueous solubility.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Antimitotic Agents/chemical synthesis , Antimitotic Agents/pharmacology , Kinesins/antagonists & inhibitors , Mitosis/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chemical Phenomena , Chemistry, Physical , Drug Design , Drug Resistance, Neoplasm , Genes, MDR/drug effects , Humans , Indicators and Reagents , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.
Subject(s)
Benzoxazines/chemistry , Benzoxazines/pharmacology , Drug Design , Kinesins/antagonists & inhibitors , Kinesins/metabolism , Mitosis/drug effects , Pyrazoles/chemistry , Animals , Benzoxazines/chemical synthesis , Benzoxazines/pharmacokinetics , Cell Line , Dogs , Humans , Hydrogen/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evidence of binding mode and in vivo potency data is also highlighted.
