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

Abstract

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.

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

“…The care and use of the animals and the experimental protocols were approved by the Experimental Animal Care and Use Committee of Takeda Pharmaceutical Company Limited. and T-773 (1-[2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one) were synthesized by Takeda Pharmaceutical Company Limited (Kunitomo et al, 2014;Yoshikawa et al, 2015). Compound 1 was referred to as compound 19e in Yoshikawa et al (2015).…”

“…Inhibitory activities of test compounds for recombinant human PDEs (1-11) were measured by scintillation proximity assay (PerkinElmer, Inc., Waltham, MA) as previously described (Kunitomo et al, 2014). Methods are described in the Supplementary Information.…”

“…Pde10a-knockout mice were used to confirm the role of PDE10A in TAK-063-and MP-10-dependent dopamine release in the striatum. In Pde10a-knockout mice, TAK-063 does not accumulate in the striatum (Harada et al, 2015a) and is not effective in reversing phencyclidine-induced hyperactivity (Kunitomo et al, 2014). The slight dopamine release by TAK-063 at 86% occupancy (3 mg/kg) was absent in Pde10a-knockout mice and the excessive dopamine release by MP-10 at 96% occupancy (30 mg/kg) was also completely abolished in Pde10a-knockout mice; thus, PDE10A inhibition appears to induce dopamine release (Figure 2f).…”

“…Both TAK-063 and MP-10 bind to the substrate-binding site in the catalytic domain of PDE10A (Kunitomo et al, 2014;Verhoest et al, 2009); thus, cAMP and cGMP levels increased by PDE10A inhibition and/or (e) Activation of MSNs by compound 1. mRNA levels of substance P (SP) and enkephalin (Enk) in the rat striatum were measured by quantitative PCR 3 h after administration of compound 1. Data are presented as mean+SEM (n = 6).…”

“…We searched selective PDE10A inhibitors with dosedependent efficacy in both METH-induced hyperactivity in rats and PPI deficits in mice and discovered the novel and highly selective PDE10A inhibitor TAK-063 (Harada et al, 2015a;Kunitomo et al, 2014). TAK-063 has some pharmacological effects in common with MP-10 (Grauer et al, 2009;Suzuki et al, 2015): increased cAMP and cGMP levels in the mouse striatum and reduced potential for induction of cataleptic responses compared with current antipsychotics.…”