Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors.

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

Identification of potent lysophosphatidic acid receptor 5 (LPA5) antagonists as potential analgesic agents.

Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities. Among these compounds, compound 7e showed potent LPA5 activity with an IC50 value of 0.12 µM, and acceptable BBB permeability. Furthermore, it showed effective analgesic effect in a chronic constriction injury rat model. Therefore, 7e may have a potential as novel pain therapeutic approach.

Addressing phototoxicity observed in a novel series of biaryl derivatives: discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436.

We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.