Abstract
ABSTRACTN-(2-pyridylmethyl)-2-hydroxiymethyl-1-pyrrolidinyl-4-(3-chloro-4-methoxy-benzylamino)-5-pyrimidine-carboxamide (NHPPC) is a new potential of type 5 phosphodiesterase (PDE5) inhibitors, synthesized from the avanafil analogue for the treatment of erectile dysfunction. The targets of this article were to assess plasma protein binding, liver microsomal metabolic stability, inhibition and induction on cytochrome P450 isozymes and the pharmacokinetics of NHPPC. Equilibrium dialysis technique was applied to determine Plasma protein binding (PPB) and NHPPC was evaluated in male Sprague–Dawley rats and Beagle dogs in vivo pharmacokinetic. The NHPPC was highly bound to plasma proteins in rats, dogs and human tested and the mean values for PPB rate were 96.2%, 99.6% and 99.4%, respectively. After in vitro liver microsomes incubated for 60 min, the percent remaining of NHPPC was 42.8%, 0.8% and 42.0% in rats, dogs and human, respectively. In vitro intrinsic clearance was found to be 0.0233, 0.1204 and 0.0214 mL/min/mg protein in rat, dog and human liver microsomes of NHPPC, respectively. NHPPC showed no significant inhibitory effects on major CYP450 enzymes, and had no significant induction potential on CYP1A2 and CYP3A4. Following oral administration in rats and dogs, tmax was 6 and 0.5 h, respectively. The clearance for NHPPC was 1.19 and 1.46 L/h/kg in rats and dogs, respectively. And absolute bioavailability in rat and dog were approximately 34.5% and 53.1%, respectively. These results showed that NHPPC has a good development prospect.
Highlights
N-(2-pyridylmethyl)-2-hydroxiymethyl-1-pyrrolidinyl-4(3-chloro-4-methoxy-benzylamino)-5-pyrimidine-carboxamide (NHPPC, Figure 1), a potential of type 5 phosphodiesterase inhibitors, was avanafil modified structural analog
The plasma stability tests of NHPPC at 0.2 and 1.0 μM, respectively, at 37°C showed that NHPPC was stable for 6 h in the rats (100.9%), dogs (100.0%) and human (100.7%) plasma, with ≥99% NHPPC remaining after the 6 h incubation
In the present work, the potential of NHPPC was investigated in preclinical evaluation of drug metabolism and pharmacokinetics
Summary
N-(2-pyridylmethyl)-2-hydroxiymethyl-1-pyrrolidinyl-4(3-chloro-4-methoxy-benzylamino)-5-pyrimidine-carboxamide (NHPPC, Figure 1), a potential of type 5 phosphodiesterase inhibitors, was avanafil modified structural analog. The preliminary efficacy experiment of rabbit model in vivo showed that NHPPC has stronger than avanafil. PDE5 inhibitors including avanafil, tadalafil, vardenafil and sildenafil have been widely accepted as first-line therapy for ED (Doggrell 2005; Yuan et al 2013) These conventional therapeutic drugs have not yet met with therapeutic purposes, and there are some adverse reactions. The novel highly selective PDE5 inhibitors with strong efficacy and fast onset of action have great significance and economic value, and improve the safe use of drugs to prevent adverse reactions. The most common adverse reactions reported in drug’s instructions are headache, dizziness, cold symptoms, flushing, nasal congestion, back pain and visual impairment It can have more severe side effects such as: change or loss of vision and/ or hearing, priapism, chest or stomach pain. In the early research stage, we need to conduct a series of in vivo and in vitro
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