Discovery of Reversible Covalent Bruton’s Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib)

Bruton’s
tyrosine kinase (BTK), a Tec family tyrosine kinase,
is critical in immune pathways as an essential intracellular signaling
element, participating in both adaptive and immune responses. Currently
approved BTK inhibitors are irreversible covalent inhibitors and limited
to oncology indications. Herein, we describe the design of covalent
reversible BTK inhibitors and the discoveries of PRN473 (11) and rilzabrutinib (PRN1008, 12). These compounds have
exhibited potent and durable inhibition of BTK, in vivo efficacy in
rodent arthritis models, and clinical efficacy in canine pemphigus
foliaceus. Compound 11 has completed phase 1 trials as
a topical agent, and 12 is in phase 3 trials for pemphigus
vulgaris and immune thrombocytopenia.