1zrb
From Proteopedia
(New page: 200px<br /> <applet load="1zrb" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zrb, resolution 1.90Å" /> '''Thrombin in complex...) |
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| - | [[Image:1zrb.gif|left|200px]]<br /> | + | [[Image:1zrb.gif|left|200px]]<br /><applet load="1zrb" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1zrb" size=" | + | |
caption="1zrb, resolution 1.90Å" /> | caption="1zrb, resolution 1.90Å" /> | ||
'''Thrombin in complex with an azafluorenyl inhibitor 23b'''<br /> | '''Thrombin in complex with an azafluorenyl inhibitor 23b'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide | + | Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenz ylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1ZRB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 062 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] Full crystallographic information is available from [http:// | + | 1ZRB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=062:'>062</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZRB OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Thrombin]] | [[Category: Thrombin]] | ||
| - | [[Category: Cook, J | + | [[Category: Cook, J J.]] |
| - | [[Category: Holahan, M | + | [[Category: Holahan, M A.]] |
| - | [[Category: Homnick, C | + | [[Category: Homnick, C F.]] |
| - | [[Category: Jr., J | + | [[Category: Jr., J J.Lynch.]] |
| - | [[Category: Krueger, J | + | [[Category: Krueger, J A.]] |
| - | [[Category: Leonard, Y | + | [[Category: Leonard, Y M.]] |
| - | [[Category: Lewis, S | + | [[Category: Lewis, S D.]] |
| - | [[Category: Lucas, B | + | [[Category: Lucas, B J.]] |
| - | [[Category: Lyle, E | + | [[Category: Lyle, E A.]] |
| - | [[Category: McMasters, D | + | [[Category: McMasters, D R.]] |
[[Category: Miller-Stein, C.]] | [[Category: Miller-Stein, C.]] | ||
| - | [[Category: Nantermet, P | + | [[Category: Nantermet, P G.]] |
| - | [[Category: Newton, C | + | [[Category: Newton, C L.]] |
| - | [[Category: Pietrak, B | + | [[Category: Pietrak, B L.]] |
| - | [[Category: Selnick, H | + | [[Category: Selnick, H G.]] |
[[Category: Singh, R.]] | [[Category: Singh, R.]] | ||
| - | [[Category: Sitko, G | + | [[Category: Sitko, G R.]] |
| - | [[Category: Stauffer, K | + | [[Category: Stauffer, K J.]] |
[[Category: Stranieri-Michener, M.]] | [[Category: Stranieri-Michener, M.]] | ||
| - | [[Category: Wallace, A | + | [[Category: Wallace, A A.]] |
| - | [[Category: White, R | + | [[Category: White, R B.]] |
| - | [[Category: Williams, P | + | [[Category: Williams, P D.]] |
[[Category: Wong, B.]] | [[Category: Wong, B.]] | ||
[[Category: Yan, Y.]] | [[Category: Yan, Y.]] | ||
| - | [[Category: Zrada, M | + | [[Category: Zrada, M M.]] |
[[Category: 062]] | [[Category: 062]] | ||
[[Category: thrombin; thrombin inhibitor complex]] | [[Category: thrombin; thrombin inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:18:22 2008'' |
Revision as of 14:18, 21 February 2008
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Thrombin in complex with an azafluorenyl inhibitor 23b
Contents |
Overview
Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenz ylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1ZRB 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.
Reference
9-hydroxyazafluorenes and their use in thrombin inhibitors., Stauffer KJ, Williams PD, Selnick HG, Nantermet PG, Newton CL, Homnick CF, Zrada MM, Lewis SD, Lucas BJ, Krueger JA, Pietrak BL, Lyle EA, Singh R, Miller-Stein C, White RB, Wong B, Wallace AA, Sitko GR, Cook JJ, Holahan MA, Stranieri-Michener M, Leonard YM, Lynch JJ Jr, McMasters DR, Yan Y, J Med Chem. 2005 Apr 7;48(7):2282-93. PMID:15801822
Page seeded by OCA on Thu Feb 21 16:18:22 2008
Categories: Homo sapiens | Single protein | Thrombin | Cook, J J. | Holahan, M A. | Homnick, C F. | Jr., J J.Lynch. | Krueger, J A. | Leonard, Y M. | Lewis, S D. | Lucas, B J. | Lyle, E A. | McMasters, D R. | Miller-Stein, C. | Nantermet, P G. | Newton, C L. | Pietrak, B L. | Selnick, H G. | Singh, R. | Sitko, G R. | Stauffer, K J. | Stranieri-Michener, M. | Wallace, A A. | White, R B. | Williams, P D. | Wong, B. | Yan, Y. | Zrada, M M. | 062 | Thrombin; thrombin inhibitor complex
