Patented PDE10A inhibitors: novel compounds since 2007

Abstract

PDE10A inhibitors will possibly be involved in the treatment of schizophrenia. The field is rapidly approaching a clinical validation of PDE10A inhibitors.

Discovery and Development of 11C-Lu AE92686 as a Radioligand for PET Imaging of Phosphodiesterase10A in the Brain

“…In rats as well as in mice, 3 H-Lu AE92686 showed high total binding levels in the striatum and low levels in the cerebellum (Fig. 3), which is in agreement with the PDE10A expression pattern.…”

“…Results: 11 C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3 H-Lu AE92686. The binding of 11 C-Lu AE92686 and 3 H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys.…”

“…Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and 11 C-labeled compounds were synthesized. 3 H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and 11 C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: 11 C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans.…”

Pharmacology of JNJ-42314415, a Centrally Active Phosphodiesterase 10A (PDE10A) Inhibitor: A Comparison of PDE10A Inhibitors with D2 Receptor Blockers as Potential Antipsychotic Drugs

“…1]. JNJ-42314415 is compared with three reference PDE10AIs pyrrolidin-1-yl]quinazoline] (Kehler and Kilburn, 2009);TP-10 [2-({4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl] phenoxy}methyl)quinolone] (Schmidt et al, 2008;Kehler and Kilburn, 2009);and MP-10 [PF-2545920 or 2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline] (Grauer et al, 2009;Kehler and Kilburn, 2009)] and eight reference D 2 receptor blockers [the azapines clozapine and olanzapine, the thiapine quetiapine, the benzisoxazole risperidone, the benzothiazole ziprasidone, the butyrophenone haloperidol, the dihydroquinolinone aripiprazole, and the fast-dissociating D 2 receptor blocker JNJ-37822681 [N-[1-(3,4-difluorobenzyl) piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine] (Langlois et al, 2012)]. …”

A comparative study of binding affinities for 6,7-dimethoxy-4-pyrrolidylquinazolines as phosphodiesterase 10A inhibitors using the linear interaction energy method

“…The active site is well characterized from X-ray crystallography as being small (<300 Å 2 ) and relatively polar [12,13]. A large number of PDE10 inhibitors have been reported (including Papaverine) [14][15][16][17][18][19][20][21], and currently more than 180 patent applications have been published [22]. Many of these are in various stages of clinical trials, but none of these inhibitors have yet reached the market [7,23].…”