Richard Jeremy Franklin

Discovery of a novel series of quinoxalines as inhibitors of c-Met kinase.

A series of quinoxaline inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and optimisation of the series was performed on the basis of this structure. Future directions for development of the series are discussed together with the identification of a novel quinoline scaffold.

Discovery of 4-Azaindoles as Novel Inhibitors of C- met Kinase.

A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed.

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.

PYRIDONE-BASED PEPTIDOMIMETIC INHIBITORS OF INTERLEUKIN-1β-CONVERTING ENZYME (ICE)

Abstract New potent, reversible inhibitors of recombinant human Interleukin-1β-converting enzyme (ICE, caspase-1) with significantly reduced peptide character are described. The compounds were designed by incorporation of pyridone and pyrimidone heterocyclic replacements for the P2-P3 amino acids of the native substrate and were optimised by manipulation of peripheral alkyl and aryl substituents.

Structure-activity relationships of phenothiazines in inhibiting lymphocyte motility as determined by a novel flow cytometric assay

Lymphocyte motility is highly dependent on rapid changes in cell shape. The human T-lymphoma cell line, MOLT-4, is constitutively shape-changing and motile, and both of these properties can be inhibited by the phenothiazine, chlorpromazine, as assessed by video analysis and migration across polycarbonate filters. In this paper, the light-scattering facility of a flow cytometer has been used to establish a simpler and more quantitative means of measuring changes in shape. By this method, the structure activity relationship (SAR) of phenothiazines and related compounds has been determined. The most active compounds had the tricyclic phenothiazine nucleus with a constrained dialkylaminoalkyl substituent at the nitrogen. The SAR for inhibition of lymphocyte motility differs from those reported for neuroleptic effects and for inhibition of PKC or calmodulin. Phenothiazine concentrations that inhibited lymphocyte shape-changing resulted in reduced F-actin concentrations. This indicates that the probable mode of action is disruption of mechanisms regulating actin polymerisation.