Michael Bryan Roe

Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives

We have synthesised and evaluated a series of anthranilamide based modulators of P-glycoprotein. These studies have identified XR9576(2), a potent inhibitor of P-glycoprotein in vitro and in vivo. The general synthesis and the SAR of these compounds are described.

Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1.

We have synthesized and evaluated a series of diketopiperazine-based inhibitors of PAI-1. These studies resulted in the identification of 34 which inhibited PAI-1 in vitro with an IC(50)=0.2 microM. The synthesis and SAR of these compounds are described.

New Benzylureas as a Novel Series of Potent, Nonpeptidic Vasopressin V2 Receptor Agonists

Vasopressin (AVP) is a hormone that stimulates an increase in water permeability through activation of V2 receptors in the kidney. The analogue of AVP, desmopressin, has proven an effective drug for diseases where a reduction of urine output is desired. However, its peptidic nature limits its bioavailability. We report herein the discovery of potent, nonpeptidic, benzylurea derived agonists of the vasopressin V2 receptor. We describe substitutions on the benzyl group to give improvements in potency and subsequent modifications to the urea end group to provide improvements in solubility and increased oral efficacy in a rat model of diuresis. The lead compound 20e (VA106483) is reported for the first time and has been selected for clinical development.

Solid and solution phase syntheses of the 2-cyanopyrrolidide DPP-IV inhibitor NVP-DPP728

DPP-IV inhibitors have been suggested as potential new treatments for type-II diabetes and 2-cyanopyrrolidides have been reported as potent DPP-IV inhibitors. Alternative synthetic approaches to one such compound, NVP-DPP728, are investigated here. One strategy is based in solution phase and is amenable to scale-up. The other is based on solid phase and is appropriate for the rapid analoging of the structural series.