Orally Active Adenosine A₁ Receptor Agonists with Antinociceptive Effects in Mice

Adenosine A₁ receptor (A₁AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A₁AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A₁AR agonists, some of which are structurally related to adenosine 5′-monophosphate (5′-AMP), a naturally occurring nucleotide that itself activates A₁AR. These novel compounds potently activate A₁AR in several orthogonal in vitro assays and are subtype selective for A₁AR over A_2AAR, A_2BAR, and A₃AR. Among them, UNC32A (<b>3a</b>) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of <b>3a</b> were completely abolished in A₁AR knockout mice, revealing a strict dependence on A₁AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (<i>K</i>_i of 36 nM for the human A₁AR) make this compound potentially suitable as a therapeutic

Exploiting an Allosteric Binding Site of PRMT3 Yields Potent and Selective Inhibitors

Protein arginine methyltransferases (PRMTs) play an important role in diverse biological processes. Among the nine known human PRMTs, PRMT3 has been implicated in ribosomal biosynthesis via asymmetric dimethylation of the 40S ribosomal protein S2 and in cancer via interaction with the DAL-1 tumor suppressor protein. However, few selective inhibitors of PRMTs have been discovered. We recently disclosed the first selective PRMT3 inhibitor, which occupies a novel allosteric binding site and is noncompetitive with both the peptide substrate and cofactor. Here we report comprehensive structure–activity relationship studies of this series, which resulted in the discovery of multiple PRMT3 inhibitors with submicromolar potencies. An X-ray crystal structure of compound <b>14u</b> in complex with PRMT3 confirmed that this inhibitor occupied the same allosteric binding site as our initial lead compound. These studies provide the first experimental evidence that potent and selective inhibitors can be created by exploiting the allosteric binding site of PRMT3