Potent N-(1,3-Thiazol-2-yl)pyridin-2-amine Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors with Excellent Pharmacokinetics and Low Affinity for the hERG Ion Channel

Mark T. Bilodeau,*† Adrienne E. Balitza,† Timothy J. Koester,† Peter J. Manley,† Leonard D. Rodman,† Carolyn Buser-Doepner,‡ Kathleen E. Coll,‡ Christine Fernandes,‡ Jackson B. Gibbs,‡ David C. Heimbrook,‡ William R. Huckle,‡ Nancy Kohl,‡ Joseph J. Lynch, Xianzhi Mao,‡ Rosemary C. McFall,‡ Debra McLoughlin,§ Cynthia M. Miller-Stein,§ Keith W. Rickert,‡ Laura Sepp-Lorenzino,‡ Jennifer M. Shipman,‡ Raju Subramanian,§ Kenneth A. Thomas,‡ Bradley K. Wong,§ Sean Yu,§ and George D. Hartman†
Departments of Medicinal Chemistry, Cancer Research, Drug Metabolism and Pharmacology, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486
J. Med. Chem., 2004, 47 (25), pp 6363–6372
DOI: 10.1021/jm049697f
Publication Date (Web): October 29, 2004
Copyright © 2004 American Chemical Society
*

 To whom correspondence should be addressed at the Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, P.O. Box 4, West Point, PA 19486. Tel (215) 652-5304; fax (215) 652-7310; e-mail mark_bilodeau@merck.com.

,
†

 Department of Medicinal Chemistry.

,
‡

 Department of Cancer Research.

,

 Department of Pharmacology.

,
§

 Department of Drug Metabolism.

Abstract

Abstract Image

A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.

View: Full Text HTML | Hi-Res PDF

Tools

History

  • Published In Issue December 02, 2004
  • Received April 23, 2004

Recommend & Share

Related Content

Other ACS content by these authors: