1ta2
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Crystal structure of thrombin in complex with compound 1
OverviewOverview
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1TA2 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
ReferenceReference
Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position., Tucker TJ, Brady SF, Lumma WC, Lewis SD, Gardell SJ, Naylor-Olsen AM, Yan Y, Sisko JT, Stauffer KJ, Lucas BJ, Lynch JJ, Cook JJ, Stranieri MT, Holahan MA, Lyle EA, Baskin EP, Chen IW, Dancheck KB, Krueger JA, Cooper CM, Vacca JP, J Med Chem. 1998 Aug 13;41(17):3210-9. PMID:9703466
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OCA- Pages with broken file links
- Homo sapiens
- Single protein
- Thrombin
- Baskin, E P.
- Brady, S F.
- Chen, I W.
- Cook, J J.
- Cooper, C M.
- Dancheck, K B.
- Gardel, S J.
- Holahan, M A.
- Krueger, J A.
- Lewis, S D.
- Lucas, B Y.
- Lumma, W C.
- Lyle, E A.
- Lynch, J J.
- Naylor-Olsen, A M.
- Sisko, J T.
- Stauffer, K J.
- Stranieri, M T.
- Tucker, T J.
- Vacca, J P.
- Yan, Y.
- 176
- Thrombin inhibitor complex