Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE)

Abstract

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50 000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration’s approval for the prophylactic treatment of HAE attacks in patients 12 years and older.

Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema

“…Changing the benzylamine P1 group to a 1-aminoisoquinoline P1 group achieved further potency advances in both 12 (benzylpyrazole P4 group) and 6 Figure 2. Oral small molecule PKa inhibitors with disclosed structures (avoralstat, 11 berotralstat, 12 ATN-249, 13,14 (benzylpyridone P4 group) while also reducing basicity from a pK a of 9.1 (calculated) with the benzylamine to a pK a of 7.5 (calculated) with the 1-aminoisoquinoline (Table 3). Ligand efficiency (LE) was maintained, and improvements in lipophilic ligand efficiency (LLE) 20 were seen between matched pairs 11 and 12 and 5 and 6.…”

“…Oral small molecule PKa inhibitors with disclosed structures (avoralstat, berotralstat, ATN-249, , sebetralstat) that have entered clinical trials.…”

Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies

“…28 Thus, vericiguat ( 12) is used to reduce cardiovascular death in patients with chronic systolic heart failure, and the drug was approved by the FDA in 2021. The molecular docking results suggested that riociguat (11) and vericiguat (12) exhibited a similar binding fashion with guanylate cyclase via reversible noncovalent interactions involving hydrogen bonding and π-π interaction. 29 Pyrazole mainly acted as a bioisostere of the aryl group to improve lipophilicity.…”

“…7b). 11 Apixaban (BMS-562247) (8) was approved by the FDA in 2012, and it is an oral, direct, and highly selective FXa inhibitor 12 that inhibits free and bound FXa and prothrombin, 13 independent of antithrombin III, for the prevention and treatment of thromboembolic disease (Fig. 8a).…”

“…Pulmonary hypertension is associated with endothelial dysfunction, impaired nitric oxide synthesis, and inadequate stimulation of the NO-sGC-cGMP pathway. 25 Riociguat (11) stimulates the NO-sGC-cGMP pathway and leads to an increase in cGMP production and subsequent vasodilation. This mechanism of action is also used by another drug, vericiguat (BAY-1021189) (12), which alleviates the need for a functional NO-sGC-cGMP axis 26 and thus contributes to the prevention of myocardial and vascular dysfunction 27 associated with reduced sGC activity in heart failure (Fig.…”