Balancing Molecular Size, Activity, Permeability, and Other Properties: Drug Candidates in the Context of Their Chemical Structure Optimization.

Chemical structure optimization is a vital part of early drug discovery projects. Starting with compounds that show activity on the target of interest, the chemical structures are subsequently optimized toward a development candidate (DC) molecule with the best chances of clinical success. However, the DCs in the context of such optimization programs, as well as detailed characterization of major limiting factors, have not been investigated in detail so far. Here, we report an analysis of the historical DC molecules at Novartis since 2005 in the context of their optimization projects. Mapping the DCs into their respective chemical optimization series, we find that these tend to be synthesized rather early in a substantial number of cases. Further analysis of structural properties, ADMET, and potency-related readouts revealed that DC compounds tend to be generally significantly smaller, more permeable, and have higher ligand efficiency than other compounds sent to in vivo PK studies, which we also show for compounds from the same chemical series. Although this might seem obvious to most practitioners in medicinal chemistry, for all of these properties, we could show that they tend to evolve in an undesired direction during structure optimization. This highlights the difficulty of successfully translating our knowledge to medicinal chemistry optimizations.

Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors.

NLRP3 is a molecular sensor recognizing a wide range of danger signals. Its activation leads to the assembly of an inflammasome that allows for activation of caspase-1 and subsequent maturation of IL-1ß and IL-18, as well as cleavage of Gasdermin-d and pyroptotic cell death. The NLRP3 inflammasome has been implicated in a plethora of diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, and cancer. In this publication, we describe the discovery of a novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. The hit (1) could be optimized into an advanced compound NP3-562 demonstrating excellent potency in human whole blood and full inhibition of IL-1ß release in a mouse acute peritonitis model at 30 mg/kg po dose. An X-ray structure of NP3-562 bound to the NLRP3 NACHT domain revealed a unique binding mode as compared to the known sulfonylurea-based inhibitors. In addition, NP3-562 shows also a good overall development profile.