Identification of two novel, potent, low-liability antinociceptive compounds from the direct in vivo screening of a large mixture-based combinatorial library.

摘要: Synthetic combinatorial methods now make it practical to readily produce hundreds of thousands individual compounds, but is clearly impractical screen each separately in vivo. We theorized that the direct vivo testing mixture-based libraries during discovery phase would enable identification novel compounds with desirable antinociceptive profiles while simultaneously eliminating many poor absorption, distribution, metabolism, or pharmacokinetic properties. The TPI 1346 small-molecule library grouped 120 mixtures derived from 26 functionalities at first three positions and 42 fourth position a pyrrolidine bis-cyclic guanidine core scaffold, totaling 738,192 compounds. These were screened using mouse 55°C warm water tail-withdrawal assay identify producing antinociception. From these data, two fully defined (TPI 1818-101 1818-109) synthesized. examined for antinociceptive, respiratory, locomotor, conditioned place preference effects. consistently demonstrated distinctly active analgesic activity was blocked by pretreatment non-selective opioid antagonist, naloxone. Based on results, synthesis 1818-109 dose-dependent effect five times greater than morphine antagonized mu- kappa-opioid receptor selective antagonists, respectively. Neither nor produced significant respiratory depression, hyperlocomotion, preference. Large, highly diverse can be directly potentially accelerating development promising therapeutics.