Structure-based Drug Design of Pyrrolidine-1, 2-dicarboxamides as a Novel Series of Orally Bioavailable Factor Xa Inhibitors

doi:10.1111/j.1747-0285.2007.00520.x

If you are seeing this message, you may be experiencing temporary network problems. Please wait a few minutes and refresh the page. If the problem persists, you may wish to report it to your local Network Manager.

It is also possible that your web browser is not configured or not able to display style sheets. In this case, although the visual presentation will be degraded, the site should continue to be functional. We recommend using the latest version of Microsoft or Mozilla web browser to help minimise these problems.

Wiley InterScience

Chemical Biology & Drug Design

Volume 69 Issue 6, Pages 444 - 450

Published Online: 6 Jun 2007

View all previous titles for this journal

< Previous Abstract | Next Abstract >

Save Article to My Profile Download Citation Request Permissions

Abstract | References | Full Text: HTML, PDF (Size: 670K) | Related Articles | Citation Tracking

Research Letter

Structure-based Drug Design of Pyrrolidine-1, 2-dicarboxamides as a Novel Series of Orally Bioavailable Factor Xa Inhibitors

Chad A. Van Huis, Christopher F. Bigge, Agustin Casimiro-Garcia*, Wayne L. Cody, Danette A. Dudley, Kevin J. Filipski, Ronald J. Heemstra, Jeffrey T. Kohrt, Lakshmi S. Narasimhan, Robert P. Schaum, Erli Zhang, John W. Bryant, Staci Haarer, Nancy Janiczek, Robert J. Leadley Jr, Thomas McClanahan, J. Thomas Peterson, Kathleen M. Welch and Jeremy J. Edmunds

Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA

Correspondence to * Agustin Casimiro-Garcia, agustin.casimiro-garcia@pfizer.com

^a FlexX® is a docking application of SYBYL® from Tripos, Inc., 1699 South Hanley Road, St Louis, MO 63144-2319, USA.

^b Other P1 groups investigated included chlorine substituted phenylacetamides, benzene-sulfonamides, and benzamides.

^c Atomic co-ordinates for the X-ray co-crystal structure of factor Xa with compound 13 have been deposited in the Protein Data Bank (ID# 2PR3).

^d LogP = the octanol-water partition coefficient of compounds at pH 10 and pH 3 by as determined by microemulsion electrokinetic chromatography. TPSA = topological polar surface area is a descriptor that correlates well with passive molecular transport through membranes. The units are Å². The algorithm for TPSA is described in Ref. (19); Cs = aqueous solubility determined by measuring the concentration of increasing aliquots of a 10 mm solution of a compound in DMSO in 50 mm sodium phosphate buffer at pH 6.5 by HPLC; P_app = the apparent permeability from A to B as determined across a CaCO-2 monolayer.

KEYWORDS

anticoagulant • antithrombotic • factor Xa • serine protease • structure-based drug design • thromboembolism • thrombosis

ABSTRACT

A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a d-proline scaffold (1, IC₅₀ = 18 nm). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC₅₀ = 0.38 nm), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.

Received 19 April 2007, revised 7 May 2007 and accepted for publication 10 May 2007

DIGITAL OBJECT IDENTIFIER (DOI)

10.1111/j.1747-0285.2007.00520.x About DOI