Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs) led to the identification of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (27h). Compound 27h has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of compound 27h to mice elevated striatal 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg. Compound 27h (TAK-063) is currently being evaluated in clinical trials for the treatment of schizophrenia.
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PMID:Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor. 2538 88

Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice.
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PMID:Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor. 2649 83