Development of Diphenyl-1,2,4-Oxadiazole Analogues as Allosteric Modulators of the RXFP3 Receptor: Evaluation of Importance of the N‑Substituted-2-Pyrrolidone Moiety in RLX-33

Relaxin-3/RXFP3 antagonism is a novel strategy for drug
development
to treat alcohol use disorder (AUD). We recently discovered the first-in-class
RXFP3 negative allosteric modulators (NAMs), represented by RLX-33,
which significantly reduced alcohol consumption in rats. In this study,
we report the design and synthesis of a series of diphenyl-1,2,4-oxadiazole
analogues derived from RLX-33. Structure–activity relationship
studies of sites A and B of RLX-33 revealed that the aromatic ring
at site A is not required for RXFP3 allosteric modulation and the
pyrrolidone linker at site B could be replaced with a cyclic or linear
alkylamine. Compound (R,R)-3 has improved potency and ADME properties (e.g., solubility
and metabolic stability) compared to RLX-33, while maintaining high
receptor subtype selectivity over RXFP1 and RXFP4. Importantly, (R,R)-3 significantly attenuated
alcohol self-administration without affecting sucrose self-administration
and general locomotor activity in rats, demonstrating the potential
of RXFP3 NAMs as promising drug candidates for AUD.