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

Authors
Soll, RM Lu, T Tomczuk, B Illig, CR Fedde, C Eisennagel, S Bone, R Murphy, L Spurlino, J Salemme, FR
Citation
Rm. Soll et al., Amidinohydrazones as guanidine bioisosteres: Application to a new class ofpotent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors, BIOORG MED, 10(1), 2000, pp. 1-4
Citations number
14
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
ISSN journal
0960894X → ACNP
Volume
10
Issue
1
Year of publication
2000
Pages
1 - 4
Database
ISI
SICI code
0960-894X(20000103)10:1<1:AAGBAT>2.0.ZU;2-8
Abstract
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, i s selective for thrombin, and shows 60 and 23% bioavailability in rabbits a nd dogs, respectively. Crystallographic analysis of 4 bound to thrombin con firmed the amindinohydrazone binding mode. (C) 1999 Published by Elsevier S cience Ltd. All rights reserved.