5DH4: Pde10 Complexed With 5-chloro-n-[(2,4-dimethylthiazol-5-yl) Methyl]pyrazolo[1,5-a]pyrimidin-7-amine

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.
PDB ID: 5DH4Download
MMDB ID: 136028
PDB Deposition Date: 2015/8/29
Updated in MMDB: 2016/01
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 5DH4: monomeric; determined by author and by software (PISA)
Molecular Components in 5DH4
Label Count Molecule
Protein (1 molecule)
Camp and Camp-inhibited Cgmp 3',5'-cyclic Phosphodiesterase 10A(Gene symbol: PDE10A)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB