| Автор | Bell, Andrew S. |
| Автор | Palmer, Michael J. |
| Дата выпуска | 2011 |
| ISBN | 978-1-84973-126-3 |
| dc.description | Clinical studies with our male erectile dysfunction medicine, sildenafil, identified several additional indications for PDE5 inhibitors. Since these include disease indications requiring chronic treatment and/or single dose daily dosing in order to be competitive, we sought novel agents with an excellent safety profile, and in particular, no potential for off-target activity against other PDE family members.We were able to identify a second generation PDE5 agent meeting these requirement based on a HTSâ derived series. Key elements in discovery were the focus on physicochemistry and pharmacokinetics throughout the programme, together with the use of co-crystal structure data to guide design and identification of a parallel chemistry amenable, wide synthetic scope template. These elements enabled rapid discovery of a proprietary lead 3 with inherently good physicochemistry, a novel aminopyridine pharmacophore and PDE6 selectivity. Further optimisation provided advanced acidic, neutral and basic leads. Finally, a potent and selective acidic clinical candidate 13 with low clearance and an outstanding safety profile was identified. The excellent pre-clinical profile derived from our property-based strategy has successfully translated to once daily oral pharmacokinetics in man. |
| Формат | application.pdf |
| Издатель | Royal Society of Chemistry |
| Название | Chapter 8. The Discovery of the Long-acting PDE5 Inhibitor PF-489791 for the Treatment of Pulmonary Hypertension |
| Тип | other |
| DOI | 10.1039/9781849731980-00166 |
| Журнал | Accounts in Drug Discovery: Case Studies in Medicinal Chemistry |
| Первая страница | 166 |
| Последняя страница | 182 |
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