Disposition of a novel and potent α_vβ₃ antagonist in animals, and extrapolation to man

Abstract

1. The disposition of 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl) propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid (compound A), a potent and selective α_vβ₃ antagonist, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development.

2. Compound A exhibited marked species differences in pharmacokinetics; the plasma clearances and bioavailabilities ranged from 33–47 ml min⁻¹ kg⁻¹ in rats and mice to 4–9 ml min⁻¹ kg⁻¹ in dogs and monkeys, and about 20% in rats to 70–80% in dogs and monkeys, respectively. Both the intravenous (i.v.) and oral kinetics of compound A were linear over the dose range studied in dogs (0.1–5 mg kg⁻¹ i.v. and 0.25–20 mg kg⁻¹ orally [p.o.]) and rats (1–30 mg kg⁻¹ i.v. and 4–160 mg kg⁻¹ p.o.).

3. Compound A was eliminated substantially by urinary excretion; the urinary recovery of the unchanged drug was 67% in rhesus, 48% in dogs and about 30% in rats. In these animal species, biotransformation was modest.

4. Following i.v. administration of [¹⁴C]-compound A to rats, the radioactivity rapidly distributed to all tissues investigated, with high levels of the radioactivity detected in liver, kidney and intestine soon after the drug administration. The radioactivity declined rapidly, with less than 1% of the i.v. dose remaining at 30-h post-dose.

5. Compound A was moderately bound to plasma proteins, with unbound fractions of 26, 20, 14 and 5% for rats, dogs, monkeys and humans, respectively. It was bound primarily to human α₁-acid glycoprotein (about 85% binding at 0.1% concentration), as compared with human albumin (< 50% binding at 4% concentration).

6. Using simple allometry, compound A was predicted to exhibit relatively low clearance (1–3 ml min⁻¹ kg⁻¹) and low volume of distribution (0.1–0.3 l kg⁻¹) in humans. Based on the predicted values, compound A was projected to exhibit a favourable oral pharmacokinetic profile in humans, with good bioavailability (50–80%). These predicted values provided a basis for compound selection for further development.