Plasma kallikrein (PKa) is a trypsin-like serine protease that has the capacity to liberate bradykinin from high molecular weight kininogen. PKa is thought to play a role in a number of inflammatory and edematous disorders including advanced diabetic macular edema, where expression of the plasma kallikrein-kinin system is abnormally abundant in ocular tissues. It has also been shown that PKa contributes to retinal vascular dysfunctions in diabetic rats and that this can be ameliorated by the delivery of systemic PKa inhibitors. Taken together, these provide a good therapeutic rationale in the ophthalmology field for the use of PKa inhibitors as a potential treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. The development of a small-molecule PKa inhibitor would provide a novel approach for the treatment of diabetic macular edema and may be efficacious in both improving symptoms of the disease, such as deteriorating visual acuity and slowing disease progression.<br/>This presentation is a first-time disclosure describing the discovery of the clinical candidate KVD001, a small-molecule PKa inhibitor, to be administered by intravitreal dosing. The initial lead molecule whilst a potent PKa inhibitor, was considered to have a short intraocular half-life. Structure-activity relationships will be described wherein the first attempts at optimisation led to drops in potency but which ultimately culminated in the identification of KVD001, a potent, competitive and reversible inhibitor of PKa with Ki = 9nM and good selectivity over closely related proteases. X-ray crystallographic studies of the inhibitor bound to the protein revealed key interactions in the active site of the enzyme but with differences from previously published crystal structures. Ocular pharmacokinetic studies in monkey following intravitreal dosing of KVD001 demonstrated a long half-life in ocular tissues and retina (and choroid) levels confirmed the compound was able to reach the posterior ocular tissues. KVD001 is a potentially first-in-class PKa inhibitor for the treatment of diabetic macular edema which has undergone a phase 2 clinical study.

Discovery of KVD001: A potent and selective small-molecule plasma kallikrein inhibitor for the treatment of diabetic macular edema

ACS Fall 2021

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