RESUMO
Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.
RESUMO
The cardiovascular and renal effects of graded i.v. dosages of two low Km cAMP cGMP-inhibitable (cGi) phosphodiesterase (PDE) inhibitors: CI-930 and milrinone (both 10-300 micrograms/kg), and three pure vasodilators: fenoldopam (0.1-3 micrograms/kg), Na nitroprusside (3-100 micrograms/kg) and hydralazine (0.1-3 mg/kg), were compared in conscious dogs. Mean arterial pressure was decreased by CI-930 at 0.3 mg/kg, milrinone at doses greater than or equal to 0.1 mg/kg (both by approximately -17 mmHg [max. change]), nitroprusside at doses greater than or equal to 0.01 mg/kg (-60 +/- 5 mmHg, [mean +/- SEM, max. change]), fenoldopam at doses greater than or equal to 0.001 mg/kg, and hydralazine at all doses (both by approximately -26 mmHg). Heart rate was increased by milrinone and CI-930 at dosages greater than or equal to 0.03 mg/kg (both by approximately 57 beats/min), nitroprusside and hydralazine at all dosages (54 +/- 18 and 91 +/- 18 beats/min, respectively) and fenoldopam at 3 micrograms/kg (21 +/- 2 beats/min). The cGi PDE inhibitors at 0.01-0.3 mg/kg and the pure vasodilators (except fenoldopam) at all dosages increased dP/dt (approximately 1500 and 900 mmHg/s, respectively). Milrinone (greater than or equal to 0.1 mg/kg), CI-930 (greater than or equal to 0.03 mg/kg), nitroprusside (greater than or equal to 0.01 mg/kg) and hydralazine (0.3-1 mg/kg) decreased left ventricular end diastolic pressure (all by approximately -4 mmHg). None of the agents adversely affected urinary volume, Na+ and K+ excretion rates. In conclusion, all agents (except fenoldopam) induced positive inotropic and chronotropic effects, and preload and afterload reduction. The cardiac effects of the pure vasodilators may be reflexly induced, whereas those of the cGi PDE inhibitors may be primarily due to inhibition of cardiac cGi PDE.