2oag
From Proteopedia
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==Overview== | ==Overview== | ||
| - | A novel series of pyrrolidine-constrained phenethylamines were developed | + | A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal. |
==About this Structure== | ==About this Structure== | ||
| Line 10: | Line 10: | ||
==Reference== | ==Reference== | ||
| - | Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit., Backes BJ, Longenecker K, Hamilton GL, Stewart K, Lai C, Kopecka H, von Geldern TW, Madar DJ, Pei Z, Lubben TH, Zinker BA, Tian Z, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Kempf-Grote AJ, Black-Schaefer C, Sham HL, Trevillyan JM, Bioorg Med Chem Lett. 2007 Jan 19 | + | Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit., Backes BJ, Longenecker K, Hamilton GL, Stewart K, Lai C, Kopecka H, von Geldern TW, Madar DJ, Pei Z, Lubben TH, Zinker BA, Tian Z, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Kempf-Grote AJ, Black-Schaefer C, Sham HL, Trevillyan JM, Bioorg Med Chem Lett. 2007 Apr 1;17(7):2005-12. Epub 2007 Jan 19. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17276063 17276063] |
[[Category: Dipeptidyl-peptidase IV]] | [[Category: Dipeptidyl-peptidase IV]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Backes, B | + | [[Category: Backes, B J.]] |
| - | [[Category: Hamilton, G | + | [[Category: Hamilton, G L.]] |
[[Category: Kopecka, H.]] | [[Category: Kopecka, H.]] | ||
[[Category: Lai, C.]] | [[Category: Lai, C.]] | ||
| - | [[Category: Longenecker, K | + | [[Category: Longenecker, K L.]] |
| - | [[Category: Stewart, K | + | [[Category: Stewart, K D.]] |
[[Category: DLI]] | [[Category: DLI]] | ||
[[Category: hydrolase]] | [[Category: hydrolase]] | ||
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[[Category: serine-peptidase]] | [[Category: serine-peptidase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:16:16 2008'' |
Revision as of 16:16, 21 February 2008
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Crystal structure of human dipeptidyl peptidase IV (DPPIV) with pyrrolidine-constrained phenethylamine 29g
Overview
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
About this Structure
2OAG is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Dipeptidyl-peptidase IV, with EC number 3.4.14.5 Full crystallographic information is available from OCA.
Reference
Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit., Backes BJ, Longenecker K, Hamilton GL, Stewart K, Lai C, Kopecka H, von Geldern TW, Madar DJ, Pei Z, Lubben TH, Zinker BA, Tian Z, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Kempf-Grote AJ, Black-Schaefer C, Sham HL, Trevillyan JM, Bioorg Med Chem Lett. 2007 Apr 1;17(7):2005-12. Epub 2007 Jan 19. PMID:17276063
Page seeded by OCA on Thu Feb 21 18:16:16 2008
