Novel orally bioavailable piperidine derivatives as extracellular arginase inhibitors developed by a ring expansion

Arginase is a multifaced enzyme that plays an important role in health and disease being regarded as a therapeutic target for the treatment of various pathological states such as malignancies, asthma, and cardiovascular disease. The discovery of boronic acid-based arginase inhibitors in 1997 revolutionized attempts of medicinal chemistry focused on development of drugs targeting arginase. Unfortunately, these very polar compounds had limitations such as analysis and purification without chromophores, synthetically challenging space, and poor oral bioavailability. Herein, we present a novel class of boronic acid-based arginase inhibitors which are piperidine derivatives exhibiting a different pharmacological profile compared to our drug candidate in cancer immunotherapy –OATD-02 – dual ARG1/2 inhibitor with high intracellular activity. Compounds from this new series show low intracellular activity, hence they can inhibit mainly extracellular arginase, providing different therapeutic space compared to a dual intracellular ARG1/2 inhibitor. The disclosed series showed good inhibitory potential towards arginase enzyme in vitro (IC50 up to 160 nM), favorable pharmacokinetics in animal models, and encouraging preliminary in vitro and in vivo tolerability. Compounds from the new series have moderate-to-high oral bioavailability (up to 66 %) and moderate clearance in vivo. Herein we describe the development and optimization of the synthesis of the new class of boronic acid-based arginase inhibitors via a ring expansion approach starting from the inexpensive chirality source (d-hydroxyproline). This upgraded methodology facilitated a gram-scale delivery of the final compound and eliminated the need for costly and time-consuming chiral resolution.