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Journals and Conferences
The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug… (More)
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large… (More)
The inhibition of the hERG channel by noncardiovascular drugs is a side effect that severely impedes the development of new medications. To increase hERG selectivity of preclinical compounds, we recommend the study of nondesolvation related interactions with the intended target and hERG using a baseline lipophilicity relationship approach. While this… (More)
One hundred and fourteen refugee children from South Vietnam showed similar disease prevalences to refugee children from Bangladesh. Common diseases were malnutrition, gastroenteritis, pneumonia and bronchitis, scabies and furunculosis. Seven children died, five from pneumonia complicated by malnutrition. Increased awareness of the high incidence of… (More)
The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and outstanding pharmacokinetics in preclinical species.
The discovery of potent small molecule dual antagonists of the human CCR3 and H(1) receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H(1) activity and in vitro metabolic… (More)
A series of dual CCR3/H(1) antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation.
1. FPL 63012AR is a D1-receptor agonist in the dog kidney, 10 times as potent as dopamine, reducing renal vascular resistance by 20% with an intra-arterial dose of 0.42 nmol kg-1. 2. No prejunctional inhibitory D2-receptor agonist activity was detected in either the isolated ear artery of the rabbit or in the conscious dog as D2-receptor-mediated emesis. 3.… (More)
The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic… (More)