5DH5

PDE10 complexed with N-[(1-methylpyrazol-4-yl)methyl]-5-[[(1S,2S)-2-(2-pyridyl)cyclopropyl]methoxy]pyrazolo[1,5-a]pyrimidin-7-amine

Summary for 5DH5

• Entry DOI: 10.2210/pdb5dh5/pdb
• Related: 5DH4
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9Y233
• Total number of polymer chains: 2
• Total formula weight: 80143.14

Authors

Yan, Y. (deposition date: 2015-08-29, release date: 2016-01-27, Last modification date: 2024-03-06)

Primary citation

Raheem, I.T.,Schreier, J.D.,Fuerst, J.,Gantert, L.,Hostetler, E.D.,Huszar, S.,Joshi, A.,Kandebo, M.,Kim, S.H.,Li, J.,Ma, B.,McGaughey, G.,Sharma, S.,Shipe, W.D.,Uslaner, J.,Vandeveer, G.H.,Yan, Y.,Renger, J.J.,Smith, S.M.,Coleman, P.J.,Cox, C.D.
Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.
Bioorg.Med.Chem.Lett., 26:126-132, 2016

PubMed Abstract: Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.

PubMed: 26602277
DOI: 10.1016/j.bmcl.2015.11.013

Experimental method

X-RAY DIFFRACTION (2 Å)