- Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position
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A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (K(i) 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.
- Feng, Dong-Mei,Gardell, Stephen J.,Lewis, S. Dale,Bock, Mark G.,Chen, Zhongguo,Freidinger, Roger M.,Naylor-Olsen, Adel M.,Ramjit, Harri G.,Woltmann, Richard,Baskin, Elizabeth P.,Lynch, Joseph J.,Lucas, Robert,Shafer, Jules A.,Dancheck, Kimberley B.,Chen, I.-Wu,Mao, Shi-Shan,Krueger, Julie A.,Hare, Timothy R.,Mulichak, Anne M.,Vacca, Joseph P.
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p. 3726 - 3733
(2007/10/03)
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- Synthesis and biological activity of ketomethylene pseudopeptide analogues as thrombin inhibitors
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Ketomethylene pseudopeptide analogues Aa-Pro-Argψ(COCH2)Gly-pip, 1, where Aa are D- or L-amino acids (Dpa, β,β-diphenylalanine; αNal, α- naphthylalanine; βNal, β-naphthylalanine; Fgl, fluorenylglycine) with highly lipophilic side chains and ψ(COCH2) is a ketomethylene pseudopeptide bond, have been synthesized through a modified Dakin-West reaction under very mild conditions with a high yield using tripeptide 4 with a labile functional group directly on the side chain. Their enzymatic assay of thrombin inhibition has been carried out. The structure-activity relationship study indicated that a lipophilic side chain on the amino acid in the P3 position is very important for binding to the apolar site of thrombin. Compound 1a with D-Dpa at the P3 position has a K(i) of 0.2 μM and it doubles thrombin clotting time at only 3 times higher concentration. These values are about 7 times better than those of the corresponding D-Phe analogues. Furthermore, 1a shows poor inhibitory activity against plasmin, factor Xa, urokinase, and kallikrein. Preliminary in vivo testing (3-4-kg rabbit as the animal model) shows no observable side effect (change of blood pressure and accumulation of blood platelet in lungs) at a dose of 1 mg/kg.
- Cheng,Goodwin,Schully,Kakkar,Claeson
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p. 3364 - 3369
(2007/10/02)
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