Mavacamten (MYK-461) is an orally bioavailable inhibitor of cardiac myosin ATPase,( IC50s of 490, 711 nM for bovine cardiac and human cardiac, respectively)

ATPase (human cardiac myosin):711 nM, ATPase (Bovine cardiac myosin):490 nM

MYK-461的研究显示，在牛体系中具有490 nM的IC50值，在人体系中为711 nM，在兔体系中为2140 nM，表明其对心脏肌球蛋白的选择性大于四倍[1]。

MYK-461 降低心脏收缩力，防止左心室肥大，并逆转病理性重塑。在猫中，它缓解左心室流出道阻塞[2]。

Five?cats received a combination of alfaxalone and midazolam for anesthetic induction, followed by inhaled isoflurane and oxygen maintenance.?Blood pressure was measured via an automated blood pressure cuff at five-minute intervals with supplementary continuous monitoring by arterial line when arterial access could be obtained.?Following induction of anesthesia, a complete baseline echocardiogram was performed (timepoint #1).?Cats were then treated with atropine 0.04 mg/kg IV, followed by an infusion of isoproterenol 0.04 μg/kg/min IV to elevate heart rate back to pre-anesthetized values and induce the previously observed LVOT obstruction.?After five to seven minutes, a stable heart rate of 200–220 bpm was reached and a complete echocardiogram was performed (timepoint #2).?At the completion of imaging, a ten-minute intravenous infusion of MYK-461 (n = 5) at 0.3 mg/kg/hr IV was started.?Focused echocardiography was performed after five minutes (timepoint #3).?After ten minutes, the MYK-461 infusion rate was lowered to 0.12 mg/kg/hr IV, a blood sample was drawn and an echocardiogram performed (timepoint #4).?If ventricular function remained hypercontractile or within normal limits by visual inspection, another blood sample was obtained and the MYK-461infusion rate was increased to 0.36 mg/kg/hr IV for ten minutes.?Focused echocardiography was performed after five minutes (timepoint #5).?After ten minutes, the MYK-461 infusion rate was lowered to 0.15 mg/kg/hr IV, a blood sample was drawn and an echocardiogram performed (timepoint #6).?Following imaging, the isoproterenol infusion was discontinued.?When heart rate returned to baseline levels (five to seven minutes), a complete echocardiogram was performed on MYK-461 alone (timepoint #7).?Study drug was then discontinued, and animals were awakened, extubated and moved to recovery.?Three of five cats were available to return for a control arm of this experiment after a 6-week washout period.The experiment was completed with identical methodology with the exception that MYK-461 was substituted for vehicle (control) at matched volumes/infusion rates[2].