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Journals and Conferences
Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a… (More)
Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8… (More)
The discovery of a potent intracellular inhibitor of human neutrophil elastase which is orally active and has a long duration of action is described. The pharmacodynamic and pharmacokinetic properties of a trans-lactam development candidate, GW311616A, are described.
Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the… (More)
Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a… (More)
The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing… (More)
Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFkappaB agonist activity was optimised in an iterative process from pIC(50) 7.5 (for 7), to pIC(50) 10.1 (for 38E1). An explanation for the SAR observed based is presented along with a proposed docking of 38E1 into the active site of the glucocorticoid receptor.
The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and… (More)