5vp0

Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive DisordersDiscovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders

Structural highlights

5vp0 is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5vp1
Activity:	3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PDE2A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.^[1] ^[2]

Publication Abstract from PubMed

Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain, and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brains, and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.

Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2 ,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders.,Mikami S, Nakamura S, Ashizawa T, Nomura I, Kawasaki M, Sasaki S, Oki H, Kokubo H, Hoffman ID, Zou H, Uchiyama N, Nakashima K, Kamiguchi N, Imada H, Suzuki N, Iwashita H, Taniguchi T J Med Chem. 2017 Aug 10. doi: 10.1021/acs.jmedchem.7b00807. PMID:28796496^[3]

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

References

↑ Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h
↑ Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435
↑ Mikami S, Nakamura S, Ashizawa T, Nomura I, Kawasaki M, Sasaki S, Oki H, Kokubo H, Hoffman ID, Zou H, Uchiyama N, Nakashima K, Kamiguchi N, Imada H, Suzuki N, Iwashita H, Taniguchi T. Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2 ,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders. J Med Chem. 2017 Aug 10. doi: 10.1021/acs.jmedchem.7b00807. PMID:28796496 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00807

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OCA

[1] Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h

[2] Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435

[3] Mikami S, Nakamura S, Ashizawa T, Nomura I, Kawasaki M, Sasaki S, Oki H, Kokubo H, Hoffman ID, Zou H, Uchiyama N, Nakashima K, Kamiguchi N, Imada H, Suzuki N, Iwashita H, Taniguchi T. Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2 ,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders. J Med Chem. 2017 Aug 10. doi: 10.1021/acs.jmedchem.7b00807. PMID:28796496 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00807

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