153862-93-2Relevant academic research and scientific papers
Discovery of 1-[2-Fluoro-4-(1 H -pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1 H -pyrazol-5-yl)pyridazin-4(1 H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor
Kunitomo, Jun,Yoshikawa, Masato,Fushimi, Makoto,Kawada, Akira,Quinn, John F.,Oki, Hideyuki,Kokubo, Hironori,Kondo, Mitsuyo,Nakashima, Kosuke,Kamiguchi, Naomi,Suzuki, Kazunori,Kimura, Haruhide,Taniguchi, Takahiko
, p. 9627 - 9643 (2014)
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.
Synthesis, characterization and analgesic activity of new 4-arylhydrazono-3-methoxymethyl-2-pyrazolin-5-ones
Ergenc,Capan,Demirdamar
, p. 118 - 124 (2007/10/03)
New 4-arylhydrazono-3-methoxymethyl-2-pyrazolin-5-ones (5a-j) and 4-arylhydrazono-3-methoxymethyl-1-phenyl-2-pyrazolin-5-ones (6a-j) were synthesized by the reaction of ten novel methyl 2-arylhydrazono-4-methoxy-3-oxobutanoates (4a-j) with hydrazine hydrate and phenylhydrazine, respectively. Treatment of 5a with acetic anhydride yielded 1-acetyl-4-arylhydrazono-3-methoxymethyl-2-pyrazolin-5-one (7). The structures of the tautomerically dynamic compounds were established by spectral data (1R, 1H-NMR, 13C-NMR, EIMS and CIMS) and elemental analysis. The analgesic activity of the title compounds was determined by the modified Koster's test. The most active compound was 4-[(4-chlorophenyl)hydrazono]-3-methoxymethyl-1-phenyl-2-pyrazolin-5-one (6c) demonstrating twice the activity (60 %) exerted by the reference drug acetylsalicylic acid (ASA, 27 %). The majority of the tested compounds were found to be more effective than ASA.
