Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein.

Hereditary angioedema (HAE), a rare genetic disorder, is associated with uncontrolled plasma kallikrein (PKa) enzyme activity leading to the generation of bradykinin swelling in subcutaneous and submucosal membranes in various locations of the body. Herein, we describe a series of potent α-amidobenzylboronates as potential covalent inhibitors of PKa. These compounds exhibited time-dependent inhibition of PKa (compound 20 IC50 66 nM at 1 min, 70 pM at 24 h). Further compound dissociation studies demonstrated that 20 showed no apparent reversibility comparable to d-Phe-Pro-Arg-chloromethylketone (PPACK) (23), a known nonselective covalent PKa inhibitor.

Posterior vitreous detachment and retinal tear - a prospective study of community referrals.

BACKGROUND: Retinal tears (RT) from posterior vitreous detachment (PVD) are an important and treatable cause of rhegmatogenous retinal detachment (RRD). Better understanding of the risk of RT from PVD will help plan urgent eye care. METHODS: Prospective observational case series over two years. Patients presenting to their optometrist, family doctor or emergency department with flashes and floaters were directed to a research clinic. History and examination, including slit-lamp biomicroscopy (SLB) and indentation indirect ophthalmoscopy (IIO), were performed by a single investigator, with two month follow-up for patients with confirmed PVD. Main outcome measures were incidence of PVD, RT, and RRD. RESULTS: 1010 patients were recruited. 896 (89%) patients had PVD at first assessment, of which 89 (8.8% of total cohort, 9.9% of PVD eyes) had RT and 8 had RRD. 21 (3%) of the remaining PVD patients developed RT in the subsequent two months and a further 9 (11%) patients with RT at initial assessment developed further tears by two months. 7 (0.7%) had asymptomatic RT in the fellow eye. 15% of RT were only visible on IIO and not SLB. Weiss ring was absent in 32% of eyes with RT. Patients with RT or RRD were more likely than 'PVD-only' eyes to have blurred or missing vision (p < 0.001), have higher rate of blue-green cataracts (p < 0.001), and longer axial lengths (p < 0.05). CONCLUSIONS AND RELEVANCE: This large, prospective study demonstrates a 9.9% rate of RT or RRD at the time of PVD, and emphasises the importance of IIO examination.

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.

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.