Year

2003

Degree Name

Doctor of Philosophy

Department

Department of Chemistry

Abstract

Antagonists of corticotropin-releasing hormone (CRH) were investigated as a means of preventing premature birth. Five ligand-derived pharmacophore models of the CRH-R1 receptor were generated using Catalyst®. Analysis of these models revealed the most important features to be a hydrogen bond acceptor, located on one of the nitrogens of a heterocyclic ring, a π-stacking feature, located on an aryl ring and three hydrophobic aliphatic features, one about the hydrophobic chain of a tertiary nitrogen and the other two in the 2- and 4-positions of an aryl ring. The Series la pharmacophore model was the most statistically valid model generated, having the highest null-total cost difference, generated from a large structurally diverse training set. Preliminary exclusion volume models were generated. Database mining was performed yielding twelve compounds as potential CRH-R1 inhibitors, however, none of these compounds showed significant activity.

A preliminary structure-activity relationship (SAR) analysis was performed in an attempt to investigate omissions from studies on the current range of antagonists. This involved the synthesis and biological testing of 42 aminopyrimidine derivatives, 31 of which were new structures. This study suggested that the anilino nitrogen, the aromatic ring and the nitrogen in the pyrimidine ring adjacent to the anilino group are all required for activity. In order to generate a more thorough analysis all the compounds from this series need to be tested.

A rigid scaffold and a series of derivatives were designed via de novo design methodologies using the pharmacophore models of the CRH-R1 receptor. Through the use of metathesis chemistry to generate a spiro centre, the synthesis of the scaffold and its derivatives was achieved. A total of 60 final and intermediate compounds were synthesised, 53 of which were new structures. The epoxidation and dihydroxylation reactions incorporated in this synthesis both yielded predominantly one diastereomer with the functional groups located on the same side as the aromatic ring of [3H]indol-2one; the mechanism for this selectivity is not known. None of the compounds tested thus far, show significant activity at CRH-R1, although some of the substituted rigid scaffolds have shown low levels of inhibition. Random biological screening showed activity against HIV reverse transcriptase, malaria and tuberculosis. In particular, the anilinopyrimidine-based compounds showed moderate activity against tuberculosis, which may be able to be further investigated.

Share

COinS