Ronald E. White

The involvement of free radicals in the mechanisms of monooxygenases

The occurrence of free radicals in the mechanisms of monooxygenases reflects the chemistry of dioxygen and the inertness of typical substrates. Thus, oxidation of such substrates requires attack by reduced dioxygen-derived free radicals. Consequently, a molecule of NAD(P)H must be invested for each substrate molecule oxidized. Furthermore, since free radicals are difficult to control, deviations from the intended reaction course are frequent. These considerations are illustrated by examination of the generation and fate of enzyme- and substrate-derived free radicals at various stages in the catalytic cycles of two monooxygenases important in xenobiotic biotransformation, dopamine beta-hydroxylase and cytochrome P-450.

Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors.

Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

Orally active prodrugs of quinoline-4-carboxylic acid angiotensin II receptor antagonists

Abstract Prodrug derivatization of a potent quinoline-4-carboxylic acid angiotensin II receptor antagonist was Undertaken as an approach to achieve improved oral activity. A dioxolenone carboxylic ester and an alkylated tetrazole prodrug both showed greater oral antihypertensive acivity in the salt-deplete spontaneously hypertensive rat and increased oral bioavailability relative to the parent compound.

Thromboxane receptor antagonist BMS-180291: A new pre-clinical lead

Abstract The synthesis and initial pharmacology of interphenylene 7-oxabicyclo[2.2.1]heptane oxazole thromboxane (TxA2) receptor antagonist BMS-180291 is described. BMS-180291 has been characterized as an orally bioavailable, potent and selective TxA2 antagonist with a long duration of action.

Oxidative activation of acylguanidine prodrugs: intestinal presystemic activation in rats limits absorption and can be inhibited by co-administration of ketoconazole

1 The disposition of acyl prodrugs was studied to improve the delivery of a guanidine-containing parent compound with poor membrane permeability and poor absorption. 2. The prodrugs were evaluated in vitro and in vivo for conversion to drug. Prodrugs were evaluated for hydrolytic or oxidative bioactivation in intestinal homogenate and rat liver S9 or microsomes. The disposition of the prodrugs in vivo was monitored in bile duct-cannulated rats. 3. Compounds with n -alkylacyl groups were efficiently bioactivated, but were hydrolysed before absorption. 4. Hydrolytic bioactivation could be blocked in vitro by branching in the alkyl chain. These compounds showed modest improvements in absorption, despite favourable permeability. Experiments with liver microsomes demonstrated efficient NADPH-dependent oxidative bioactivation, which was proposed to occur through a CYP-mediated side chain oxidation followed by cyclization and release of parent compound. Ketoconazole co-administration yielded approximately a twofold increase in absorption. 5. The hydrolytically stable prodrugs were successful in increasing absorption of parent drug and were efficiently bioactivated, but they did not yield increased systemic levels of drug.

Rat PXR reporter-gene activity correlates with the induction of CYP3A in rat precision-cut liver slices.

Recent studies have suggested that both constitutive androstane receptor (CAR) and pregnane X-receptor (PXR) are involved in the induction of rat liver microsomal cytochrome P-450 (CYP) 2B and 3A through a mechanism called cross-talk. In this study we intend to determine if a PXR-reporter gene assay could be used for the prediction of CYP3A and/or CYP2B induction in rats. The induction of rat CYP2B and CYP3A by nineteen structurally diverse compounds was evaluated by using rat precision-cut liver slices and a rat PXR reporter-gene system. Induction of CYP2B and CYP3A mRNAs in rat liver slices was quantified by real-time polymerase chain reaction. Rat PXR activation was measured by induction of luciferase activity in rat PXR reporter-gene system. Linear regression analysis of the fold of induction of mRNA in liver slices and the fold of luciferase activity in rat PXR reporter-gene system shows that a reasonable correlation (r2 = 0.6) exists between the CYP3A induction and the rat PXR activation. A much lower correlation was observed between CYP2B induction and the rat PXR activation (r2 = 0.1). The results from this study suggest that the PXR may play a major role in the induction of rat CYP3A, but not CYP2B. Therefore, the PXR-reporter gene assay may be useful in a high-throughput screening to predict CYP3A induction in rats.

BMS-871: A novel orally active pan-Notch inhibitor as an anticancer agent

This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.