Asymmetric preference of serine proteases toward phosphonate and phosphinate esters

We have previously reported the asymmetric synthesis of (alpha-aminoalkyl) diphenylphosphonate and phosphinate derivatives designed as inhibitors of c hymotrypsin- and elastase-like proteases. This paper reports the first kine tic evaluation of individual epimers of the (alpha-aminoalkyl) diphenylphos phonates as inactivators of chymotrypsin, cathepsin G and neutrophil elasta se (HNE). Results show that the (R)-epimers consistently function as more p otent irreversible inactivators of their respective target proteases than t he corresponding (S)-epimers. Additionally, phosphinate analogues were foun d to be consistently superior to their diphenylphosphonate counterparts. Fo r example, Cbz . Phe(P)(OPh)-(CH2)(2)-CO2Et inactivates cathepsin Gr approx imately 45-fold more rapidly (k(i)/K-i = 1.2 x 10(5) M-1.min(-1)) than the analogous Cbz.Phe(P)(OPh)(2) (2.6 x 10(8) M-1.min(-1)). Similarly, Cbz.Val( P)(OPh)-(CH2)(2)-CO2Et was found to inactivate HNE some 3-fold more efficie ntly than Cbz.ValP(OPh), (6.5 x 10(3) and 2.0 x 10(3) M-1.min(-1), respecti vely). (C) 2000 Academic Press.