Our optimization strategy in medicinal chemistry involved a multiple-parameter optimization (MPO) methodology for all newly designed and synthesized analogues of DL-175. This approach encompasses the design of new compounds with MPO scores that meet specific criteria, including: HBD≤1, TPSA≤75 Å, cLog P< 3, logD7.4 between 1 and 3, pKa<8. These criteria aligned with the requirements for favourable pharmacokinetic (PK) attributes and oral bioavailability. We also looked for correlations between binding affinity and key compound metrics such as ligand lipophilic efficiency (LLE) for all our derivatives. We also monitored the fraction of sp3 carbon atoms (Fsp3) and attempted to limit the number of aromatic rings (Property Forecast Index, PFI), which provided the favourable drug-like properties of compounds. Monitoring structure-property relationships (SPR) in this way, yielded two novel analogues with exceptional cAMP potency and a tremendous G-protein signalling bias compared to DL-175. Moreover, exquisite selectivity at GPR84 was observed in a panel against FFA1, FFA4 and CB2. In vitro metabolism studies of two new analogues showed enhanced MLM stability. In a PK experiment dosed at 10 mg/kg to a male C57BL/6J mouse, both compounds showed an appropriate ADME profile. Our two new compounds are the first drug-like biased agonist of GPR84 to serve as an in vivo pharmacological probe to perform key proof-of-concept experiments in relevant animal disease models.
Overall, the project has successfully achieved the following results:
1. Successful replacement of metabolically unstable naphthalene bottom groups of our previous compound DL-175 with highly stable aromatic rings.
2. Introduction of a strategically positioned hydroxyl group on the 3rd position of pyridine N-oxide, resulting in a 4000-fold increase in potency compared to DL-175, while remaining inactive in β-arrestin assays.
3. Discovery of the newly identified compounds AR-198 and AR-211, characterized by exceptional in vitro ADME profiles, in vivo PK profiles, high selectivity, and favourable oral bioavailability.
