Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability

In order to overcome several limitations of our lead compound, which possessed a fluorenyl side chain in P3, we synthesized a series of analogs where we systematically truncated this fluorenyl side chain. This resulted in a series of compounds with progressively smaller aliphatic side chains inhabit...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-08, Vol.14 (16), p.4161-4164
Main Authors: Morrissette, Matthew M, Stauffer, Kenneth J, Williams, Peter D, Lyle, Terry A, Vacca, Joseph P, Krueger, Julie A, Lewis, S.Dale, Lucas, Bobby J, Wong, Bradley K, White, Rebecca B, Miller-Stein, Cynthia, Lyle, Elizabeth A, Wallace, Audrey A, Leonard, Yvonne M, Welsh, Denise C, Lynch, Joseph J, McMasters, Daniel R
Format: Article
Language:English
Subjects:
Administration, Oral
Antithrombins - administration & dosage
Antithrombins - pharmacokinetics
Antithrombins - pharmacology
Biological and medical sciences
Biological Availability
Blood. Blood coagulation. Reticuloendothelial system
Drug Stability
Medical sciences
Molecular Weight
Pharmacology. Drug treatments
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Summary:In order to overcome several limitations of our lead compound, which possessed a fluorenyl side chain in P3, we synthesized a series of analogs where we systematically truncated this fluorenyl side chain. This resulted in a series of compounds with progressively smaller aliphatic side chains inhabiting P3. These changes dialed out the undesired properties of the fluorenyl side chain while maintaining thrombin inhibition and desired pharmacokinetics. Subsequent elaboration of the proline P2 unit with an azetidine unit maintained these effects while increasing metabolic stability. Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to the identification of two optimized compounds, 14 and 16.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.06.030