Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

J S Plummer; K A Berryman; C Cai; W L Cody; J DiMaio; A M Doherty; J J Edmunds; J X He; D R Holland; S Levesque; D R Kent; L S Narasimhan; J R Rubin; S T Rapundalo; M A Siddiqui; A J Susser; Y St-Denis; P D Winocour

doi:10.1016/s0960-894x(98)00613-1

Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

Bioorg Med Chem Lett. 1998 Dec 1;8(23):3409-14. doi: 10.1016/s0960-894x(98)00613-1.

Authors

J S Plummer¹, K A Berryman, C Cai, W L Cody, J DiMaio, A M Doherty, J J Edmunds, J X He, D R Holland, S Levesque, D R Kent, L S Narasimhan, J R Rubin, S T Rapundalo, M A Siddiqui, A J Susser, Y St-Denis, P D Winocour

Affiliation

¹ Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.

PMID: 9873743
DOI: 10.1016/s0960-894x(98)00613-1

Abstract

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.

MeSH terms

Animals
Fibrinolytic Agents / chemical synthesis*
Fibrinolytic Agents / pharmacology
Lactams / chemical synthesis*
Lactams / pharmacology
Rats
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / pharmacology
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*

Substances

Fibrinolytic Agents
Lactams
Serine Proteinase Inhibitors
Thrombin