ATX, as an extracellular enzyme, is a very attractive drug candidate for reducing the abun‐ dance of extracellular LPA and subsequent signaling.
There are numerous, small, non-lipid inhibitors of ATX that have been modified to increase potency . These inhibitors tend to have better bioavailability because of decreased hydrophobicity and they are unlikely to be rapidly degraded by endogenous hydrolytic pathways . One of these is PF-8380, which is a piperazinylbenzoxazolone derivative that was developed by Pfizer from compound library screening and optimization. PF-8380 has an IC50 of 2.8 nM against recombinant human ATX and 101 nM for ATX in human whole blood. It was the first ATX inhibitor that was reported to decrease plasma LPA levels in vivo for an extended period. In rat air-pouch models, 30 mg/kg PF-8380 inhibited inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen, a routinely used nonsteroidal antiinflammatory drug. This dosage of PF-8380 produced a maximum decrease in LPA concentrations in plasma and also at the site of inflammation. Like BrP-LPA, PF-8380 had radio-sensitizing effects in a heterotopic mouse model of glioblastoma multiforme, delaying tumor growth by at least 20 days.
We synthesized PF-8380 for one of our customers for reaserch use, in the synthesis, we develop a process route which can produce the compound at kg scale in one batch. The purity of PF-8380 is more than 98% by HPLC.
1HNMR, LC-MS and COA will also be provided if you order from us.
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