Michael Dennis Dowle

The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase-GW311616A a development candidate

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.

Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams

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 introduction of 9 as an intracellular neutrophil elastase inhibitor.

Syntheses of templates derived from pyrrolidine trans-lactams as potential serine protease inhibitors

The synthesis of templates derived from pyrrolidine trans-lactams as potential serine protease inhibitors is described.

Synthetic and structural studies on 1,2,4-dithiazolidine-3,5-dione derivatives

Methods have been developed for the N-alkylation of 1,2,4-dithiazolidine-3,5-dione 2 and the subsequent conversion of the N-alkylated derivatives into isocyanates 5. An extension of this methodology onto a solid-support is also reported. X-ray crystallographic analysis has been carried out on potassium 1,2,4-dithiazolidine-3,5-dione 3 for structural comparison with the parent heterocycle 2.

The iodo-lactones derived from norborn-5-en-2-endo-yl-acetic acid and -propionic acid

The iodolactonisation of norborn-5-en-2-endo-ylacetic acid is analogous to that of norborn-5-ene-2-endo-carboxylic acid and affords 6-endo-hydroxy-5-exo-iodonorbornan-2-endo-ylacetic acid δ-lactone. The lactone ring is probably in a boat conformation. The iodolactonisation of 3-(norborn-5-en-2-endo-yl)propionic acid does not follow a similar pattern; the rearrangement product obtained is 3-(2-endo-hydroxy-7-anti-iodo-norbornan-2-exo-yl)propionic acid γ-lactone.

1,2,4-Dithiazolidine-3,5-dione as an isocyanate equivalent in the Mitsunobu reaction

1,2,4-Dithiazolidine-3,5-dione 1 can be used as a nitrogen nucleophile in a modified Mitsunobu procedure to give N-alkylated products 2 which can be converted via isocyanates, into amine derivatives, under very mild conditions.

Corrigendum to “Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams”: [Bioorg. Med. Chem. Lett. 11 (2001) 243]

Simon J. F. Macdonald,* Michael D. Dowle, Lee A. Harrison, Julie E. Spooner, Pritom Shah, Martin R. Johnson, Graham G. A. Inglis, Geoffrey D. E. Clarke, David J. Belton, Robin A. Smith, Christopher R. Molloy, Mary Dixon, Graham Murkitt, Rosalind E. Godward, Tadeusz Skarzynski, Onkar M. P. Singh, K. Abhhilash Kumar, Simon T. Hodgson, Edward McDonald, George W. Hardy, Harry Finch, Davina C. Humphreys and Gill Fleetwood

The acid-catalysed lactonisation of the norborn-5-en-2-ylacetic acids

Saurekatalysierte Lactonisierung der Titelverbindung (I) oder eines 10:1-Gemisches von (I) mit seinem exo-Isomeren (IV) liefert jeweils die Lactame (II) und (III) als Gemische, deren prozentuale Zusammensetzung von der Reaktionsdauer bestimmt wird [(III) 57 ist thermodynamisch stabiler und wird bei langerer Reaktionsdauer uberwiegendes Produkt].