title: 1,2-Benzothiazine 1,1-dioxide P(2)-P(3) peptide mimetic aldehyde calpain I inhibitors.
abstract: 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 (IC(50) = 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.
authors.affiliation: Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380-4245, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Wells
authors.forename: M
authors.initials: M
authors.lastname: Tao
authors.forename: K A
authors.initials: KA
authors.lastname: Josef
authors.forename: R
authors.initials: R
authors.lastname: Bihovsky
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002154:Calpain / Q000737:chemistry* / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000447:Aldehydes; D003499:Cyclic S-Oxides; C438594:N-(3,4-dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)phenylalaninal 1,1-dioxide; D010455:Peptides; D011480:Protease Inhibitors; D013843:Thiazines; D010649:Phenylalanine; D002154:Calpain