Abstract:
A pharmacokinetic/pharmacodynamic (PK–PD) model, developed to explicitly consider drug extravascular transport (EVT), has been used to identify improved benzotriazine dioxide (BTO) analogs of the hypoxia-activated prodrug (HAP) tirapazamine. A collection of 280 BTOs was evaluated using the PK–PD model to efficiently identify 18 BTO analogs with in vivo activity. The lead compound, SN30000, has improved aqueous solubility, hypoxic cytotoxic potency, and selectivity and increased EVT in vitro. These improvements translate into increased activity against hypoxic tumor cells in vivo in combination with radiation. SN30000 has completed preclinical development and is ready to advance to clinical evaluation. This PK–PD-guided strategy has potential for the lead optimization of other HAPs.