82564-29-2Relevant articles and documents
Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A)
Hu, Essa,Kunz, Roxanne K.,Chen, Ning,Rumfelt, Shannon,Siegmund, Aaron,Andrews, Kristin,Chmait, Samer,Zhao, Sharon,Davis, Carl,Chen, Hang,Lester-Zeiner, Dianna,Ma, Ji,Biorn, Christopher,Shi, Jianxia,Porter, Amy,Treanor, James,Allen, Jennifer R.
, p. 8781 - 8792 (2013/12/04)
Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.
Orthogonal Cu- and Pd-based catalyst systems for the O- and N-arylation of aminophenols
Maiti, Debabrata,Buchwald, Stephen L.
supporting information; experimental part, p. 17423 - 17429 (2010/03/25)
O- or N-arylated aminophenol products constitute a common structural motif in various potentially useful therapeutic agents and/or drug candidates. We have developed a complementary set of Cu- and Pd-based catalyst systems for the selective O- and N-arylation of unprotected aminophenols using aryl halides. Selective O-arylation of 3- and 4-aminophenols is achieved with copper-catalyzed methods employing picolinic acid or CyDMEDA, trans-N,N′-dimethyl-1,2- cyclohexanediamine, respectively, as the ligand. The selective formation of N-arylated products of 3- and 4-aminophenols can be obtained with BrettPhos precatalyst, a biarylmonophosphine-based palladium catalyst. 2-Aminophenol can be selectively N-arylated with CuI, although no system for the selective O-arylation could be found. Coupling partners with diverse electronic properties and a variety of functional groups can be selectively transformed under these conditions.
