Introduction. CaMKIId is a validated drug target in atrial fibrillation (AF), ventricular arrhythmia, and HF. As a key mediator of Ca action, it is hyperactivated by dysregulated Ca homeostasis with pathological consequences, which can be normalized by a variety of genetic and pharmacological manipulations.Objectives. Develop an ATP competitive CaMKIId inhibitor with nanomolar potency for initial efficacy in an AF mouse model and further optimization of selectivity, PK and low CNS penetration.Methods and Results. Molecular modeling using the crystal structure of human CaMKIId with several scaffolds as a starting point, led to development of a consistent structure activity relationship model and design of AS283. The molecule is an ATP competitive inhibitor with an IC50 of 6nM and Ki of 1nM. Unlike KN-93, a common tool inhibitor of CaMKII in preclinical studies, AS283 inhibits the autophosphorylated, Ca-independent form of the kinase. AS283 shows preclinical proof of concept in both ventricular arrhythmia and AF models, with the latter described here. Mice with a gain of function mutation in the RyR2 receptor (R) do not undergo spontaneous AF but have an increased vulnerability to AF in response to atrial pacing. Intracardial electrophysiology with recording of atrial and ventricular electrograms (Na Li and Xander Wehrens, Baylor College) were used to select mutant and wild-type mice that exhibited AF in pacing trials. AF-positive animals were randomly assigned to treatment with placebo or AS283, with KN-93 as control. AS283 completely suppressed incidence of AF in comparison to placebo and exhibited a dose response. Autophosphorylation of CaMKIId at Thr287 was used as a biomarker of target engagement. As anticipated, atrial pacing increases intracellular Ca leading to activation of CaMKII and increased P-Thr287. AS283 blocked the increase in P-Thr287.Conclusion. AS283 is a novel, potent CaMKIId inhibitor with robust preclinical efficacy, supporting its further optimization for PK and low CNS penetration. Consistent with studies using genetic and pharmacological tools, an optimized, small molecule inhibitor of CaMKII has a promise in treating arrhythmias that are sub-optimally managed with or contraindicated to beta blockers.