Lee Andrew Harrison

A novel series of arylpiperazines with high affinity and selectivity for the dopamine D3 receptor

Abstract A novel series of arylpiperazines has been synthesised which show high affinity for dopamine D 3 receptors. Several of these compounds exhibit ca . 100 fold selectivity for the dopamine D 3 receptor over D 1 , D 2 and D 4 receptors. In vivo studies suggest that 4 (GR103691) may have an atypical antipsychotic profile.

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.

Discovery of a Brain-Penetrant S1P3-Sparing Direct Agonist of the S1P1 and S1P5 Receptors Efficacious at Low Oral Dose

2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RRMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P(5) agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (<1 mg p.o. once daily).

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.

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