912773-22-9Relevant articles and documents
Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders
Mikami, Satoshi,Sasaki, Shigekazu,Asano, Yasutomi,Ujikawa, Osamu,Fukumoto, Shoji,Nakashima, Kosuke,Oki, Hideyuki,Kamiguchi, Naomi,Imada, Haruka,Iwashita, Hiroki,Taniguchi, Takahiko
, p. 7658 - 7676 (2017/10/06)
Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA). Combining these structural elements led to the identification of 6-methyl-N-((1R)-1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (38a), a molecule with the desired balance of preclinical properties. Further characterization by cocrystal structure analysis of 38a bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound 38a significantly elevated 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brain following oral administration, thus validating this compound as a useful pharmacological tool and an attractive lead for future optimization.
HETEROCYCLIC COMPOUND
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Paragraph 1204; 1205, (2016/06/28)
A compound represented by the formula (I): wherein each symbol is as described in the SPECIFICATION, or a salt thereof has a PDE2A inhibitory action, and is useful as a prophylactic or therapeutic drug for schizophrenia, Alzheimer's disease and the like.
PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
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Page/Page column 91, (2012/02/01)
Compounds of the formula I or II: wherein X, m, Ar, R1 and R2 are as defined herein. The subject compounds are useful for treatment of IRAK-mediated conditions.