Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)
详细信息 查看全文
- 作者：Neil J. Press ; Roger J. Taylor ; Joseph D. Fullerton ; Pamela Tranter ; Clive McCarthy ; Thomas H. Keller ; Nicola Arnold ; David Beer ; Lyndon Brown ; Robert Cheung ; Julie Christie ; Alastair Denholm ; Sandra Haberthuer ; Julia D. I. Hatto ; Mark Keenan ; Mark K. Mercer ; Helen Oakman ; Helene Sahri ; Andrew R. Tuffnell ; Morris Tweed ; Alexandre Trifilieff
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：September 10, 2015
- 年：2015
- 卷：58
- 期：17
- 页码：6747-6752
- 全文大小：376K
- ISSN：1520-4804
文摘
Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.