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Building on a previously disclosed PDE4 inhibitor,NVP-ABE171 (1),new compounds were synthesised with significant improvements in physico-chemical properties pharmacokinetics and therapeutic index.Thus,NVP-ABE171 was a low solubility (pH 6.8=0.002g/L; pH l=0.00004g/L) compound with highly variable bioavailability (rat BAV=10% +/-5%).Rational optimisation ofphysico-chemical properties led to the synthesis of several development candidates with much improved solubility (>10g/L) and pharmacokinetic parameters (rat BAV 65-97%).Potency at the PDE4 enzyme was retained (IC50<100nM) and excellent in vivo efficacy was demonstrated in several models of inflammation.Screening for toxicological side effects was carried out in the rat and the ferret model of emesis,and led to the nomination of the compound with the greatest therapeutic ratio for further development.