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8di4

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Discovery of MK-8189, a highly potent and selective PDE10A inhibitor for the treatment of schizophrenia

Structural highlights

8di4 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.016Å
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

PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.

Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia.,Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, Hayes RP, Huszar S, Eddins D, Ma B, Fuerst J, Wollenberg GK, Li J, Fritzen J, McGaughey GB, Uslaner JM, Smith SM, Coleman PJ, Cox CD J Med Chem. 2023 Jan 26;66(2):1157-1171. doi: 10.1021/acs.jmedchem.2c01521. Epub , 2023 Jan 9. PMID:36624931^[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
↑ Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, Hayes RP, Huszar S, Eddins D, Ma B, Fuerst J, Wollenberg GK, Li J, Fritzen J, McGaughey GB, Uslaner JM, Smith SM, Coleman PJ, Cox CD. Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia. J Med Chem. 2023 Jan 26;66(2):1157-1171. PMID:36624931 doi:10.1021/acs.jmedchem.2c01521