1,2-Benzothiazine 1,1-Dioxide P2−P3 Peptide Mimetic Aldehyde Calpain I Inhibitors

A series of peptide mimetic aldehyde inhibitors of calpain I was prepared in which the P2 and P3 amino acids were replaced by substituted 3,4-dihydro-1,2-benzothiazine-3-carboxylate 1,1-dioxides. The effect of 2, 6, and 7-benzothiazine substituents and the P1 amino acid was examined. Potency of these inhibitors, 15c − p, against human recombinant calpain I is particularly dependent upon the 2-substituent, with methyl and ethyl generally more potent than hydrogen, isopropyl, isobutyl, or benzyl. The more potent diastereomer of 15m possesses the (S) absolute configuration at the 3-position of the 3,4-dihydro-1,2-benzothiazine. Potency of the best inhibitors in this series (IC50 = 5−7 nM) compares favorably with that of conventional N-benzyloxycarbonyl dipeptide aldehyde inhibitors bearing l-Leu or l-Val residues at P2. The achiral unsaturated 1,2-benzothiazine analogues 26a − d are also potent calpain I inhibitors, while 3,4-dihydro-2,1-benzoxathiin (15a,b), 1,2,4-benzothiadiazine (32a,b), and tetrahydroisoquinolinone (36a,b) analogues are less potent.