Amidinohydrazones as guanidine bioisosteres: application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors

✍ Scribed by Richard M. Soll; Tianobao Lu; Bruce Tomczuk; Carl R. Illig; Cynthia Fedde; Stephen Eisennagel; Roger Bone; Larry Murphy; John Spurlino; F.Raymond Salemme

• Book ID: 104364918
• Publisher: Elsevier Science
• Year: 2000
• Tongue: English
• Weight: 228 KB
• Volume: 10
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/s0960-894x(99)00632-0

✦ Synopsis

We describe a new class of potent, non-amide-based small molecule thrombin inhibitors in which an amidinohydrazone is used as a guanidine bioisostere on a non-peptide scaffold. Compound 4 exhibits nM inhibition of thrombin, is selective for thrombin, and shows 60 and 23% bioavailability in rabbits and dogs, respectively. Crystallographic analysis of 4 bound to thrombin confirmed the amindinohydrazone binding mode.