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 P-2 and P-3 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 P-1 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 P-2. 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.