Development of a novel class of potent and selective FIXa inhibitors

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• 作者：Ting Zhang^a ; ^{ting_zhang3@merck.com" class="auth_mail" title="E-mail the corresponding author} ; Patrick Andre^b ; Thomas J. Bateman^c ; Yi-Heng Chen^a ; Kunal Desai^b ; Kenneth Ellsworth^d ; Wayne M. Geissler^d ; Liangqin Guo^a ; Alan Hruza^e ; Tianying Jian^a ; Dongfang Meng^a ; Dann L. Parker Jr.^a ; Xiaoxia Qian^a ; Paul Reichert^e ; Edward C. Sherer^f ; Min Shu^a ; Cameron J. Smith^a ; Lisa M. Sonatore^d ; Richard Tschirret-Guth^c ; Andrew F. Nolting^g ; Robert Orr^g ; Louis-Charles Campeau^g ; Kazuto Araki^h ; Teruyuki Nishimura^h ; Isao Sakurada^h ; Harold B. Wood^a
• 关键词：Benzimidazole ; FIXa inhibitor ; TGA ; Structure based drug design
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：25
• 期：21
• 页码：4945-4949
• 全文大小：2813 K

文摘

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.