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P3 optimization of functional potency, in vivo efficacy and oral bioavailability in 3-aminopyrazinone thrombin inhibitors bearing non-charged groups at the P1 position |
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| Authors: | Isaacs Richard C A Newton Christina L Cutrona Kellie J Mercer Swati P Dorsey Bruce D McDonough Colleen M Cook Jacquelynn J Krueger Julie A Lewis S Dale Lucas Bobby J Lyle Elizabeth A Lynch Joseph J Miller-Stein Cynthia Michener Maria T Wallace Audrey A White Rebecca B Wong Bradley K |
| Affiliation: | a Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA b Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA c Department of Pharmacology Merck Research Laboratories, West Point, PA 19486, USA d Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA |
| Abstract: | Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position. |
| Keywords: | Thrombin Inhibitor Coagulation Efficacy |
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