Doreen Mary Ashworth

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.

Synthetic inhibitors of human tissue kallikrein

We have developed a series of novel, potent low molecular weight (4-600 Da) inhibitors of TK which were stable to cleavage by the enzyme and showed a high degree of selectivity for TK over several other serine proteases. Compound 7 (CH-2856) was found to reduce eosinophilia in a model of allergic inflammation. The effects observed in vivo provide further evidence for the involvement of TK and kinins in the pathophysiology of allergic diseases such as asthma.

Selective inhibitors of plasma kallikrein

Based on a tetrapeptide fragment [Pro387-Ser390] of HK we have developed a series of potent low molecular weight (5-600 Da) inhibitors of PK which are stable to the enzyme. These inhibitors show good selectivity for PK versus tissue kallikrein, thrombin and plasmin. Such inhibitors will help define the role of PK and kinins in human physiology and pathophysiology. They may also find clinical use in the treatment of diseases where kinins are important mediators.