ABSTRACT
A series of N1-alkyl pyrimidinediones were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our efforts identified compound 10b, which represents the lead compound in this series with pharmacokinetics and antiviral potency that may support once-daily dosing.
Subject(s)
Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/chemistry , Pyrimidinones/chemistry , Reverse Transcriptase Inhibitors/chemistry , Thymine/analogs & derivatives , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Dogs , HIV Reverse Transcriptase/metabolism , Humans , Microsomes/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Thymine/chemical synthesis , Thymine/chemistry , Thymine/pharmacokineticsABSTRACT
Novel analogs of (-)-saframycin A are described. The analogs are shown to be potent inhibitors of the in vitro growth of several tumor cells in a broad panel and promising as leads for further optimization. The first in vivo studies in a solid tumor model (HCT-116) reveal potent antitumor activity with associated toxicity of daily administration.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Isoquinolines/pharmacology , Mice , Mice, Inbred BALB C , Molecular Structure , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.
