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4p0n

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Revision as of 13:25, 4 August 2016

Crystal structure of PDE10a with a novel Imidazo[4,5-b]pyridine inhibitor

Structural highlights

4p0n is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PDE10_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.^[1]

Publication Abstract from PubMed

We report the discovery of novel imidazo[4,5-b]pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole 1, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailability. To improve oral bioavailability, we turned to novel scaffold imidazo[4,5-b]pyridine 2, which not only retained nanomolar PDE10A activity but was also devoid of the morpholine metabolic liability. Structure-activity relationship studies were conducted systematically to examine how various regions of the molecule impacted potency. X-ray cocrystal structures of compounds 7 and 24 in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and structurally diverse imidazo[4,5-b]pyridines (4, 7, 12b, 24a, and 24b) with PDE10A IC50 values ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies. Four of them (4, 12b, 24a, and 24b) achieved 55-74% RO at 10 mg/kg po.

Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).,Hu E, Andrews K, Chmait S, Zhao X, Davis C, Miller S, Hill Della Puppa G, Dovlatyan M, Chen H, Lester-Zeiner D, Able J, Biorn C, Ma J, Shi J, Treanor J, Allen JR ACS Med Chem Lett. 2014 Mar 28;5(6):700-5. doi: 10.1021/ml5000993. eCollection, 2014 Jun 12. PMID:24944747^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. Epub 2007 Mar 26. PMID:17389385
↑ Hu E, Andrews K, Chmait S, Zhao X, Davis C, Miller S, Hill Della Puppa G, Dovlatyan M, Chen H, Lester-Zeiner D, Able J, Biorn C, Ma J, Shi J, Treanor J, Allen JR. Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A). ACS Med Chem Lett. 2014 Mar 28;5(6):700-5. doi: 10.1021/ml5000993. eCollection, 2014 Jun 12. PMID:24944747 doi:http://dx.doi.org/10.1021/ml5000993

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4p0n"

Categories: Chmait, S | Hydrolase-hydrolase inhibitor complex

@@ Line 1: / Line 1: @@
 ==Crystal structure of PDE10a with a novel Imidazo[4,5-b]pyridine inhibitor==
 <StructureSection load='4p0n' size='340' side='right' caption='[[4p0n]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[4p0n]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4P0N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4P0N FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1IR:N-[CIS-3-(2-METHOXY-3H-IMIDAZO[4,5-B]PYRIDIN-3-YL)CYCLOBUTYL]-1,3-BENZOTHIAZOL-2-AMINE'>1IR</scene>, <scene name='pdbligand=1IS:N-[TRANS-3-(2-METHOXY-3H-IMIDAZO[4,5-B]PYRIDIN-3-YL)CYCLOBUTYL]-1,3-BENZOTHIAZOL-2-AMINE'>1IS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4p0n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p0n OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4p0n RCSB], [http://www.ebi.ac.uk/pdbsum/4p0n PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4p0n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p0n OCA], [http://pdbe.org/4p0n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4p0n RCSB], [http://www.ebi.ac.uk/pdbsum/4p0n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4p0n ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 16: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4p0n" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4p0n

From Proteopedia

Revision as of 13:25, 4 August 2016

Crystal structure of PDE10a with a novel Imidazo[4,5-b]pyridine inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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