title: New cathepsin d inhibitors with hydroxyethylamine isosteres: preparation and characterization.
abstract: The lysosomal aspartyl protease, cathepsin D, has been suggested to play a role in the metastatic potential of several types of cancer. Cathepsin D is secreted by malignant cells, and is believed to be involved in the breakdown of the extracellular matrix. High levels of active cathepsin D have been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. Also cathepsin D has recently been associated with the development of Alzheimer's disease. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases similar to cathepsin D in activity, such as the HIV-1 aspartyl protease. In the present study twenty-eight compounds containing (hydroxyethyl)amine isosteres with cyclic tertiary amines have been synthesized. These compounds show significant activity as cathepsin D inhibitors, many with IC(50) values in the nanomolar range. For example, the compounds that contain hydroxyethylamines where the amine is formed from N-piperazine-2-carboxylic acid methyl ester, 4y-bb, show IC(50) values ranging from 2.5 to 15 nM.
authors.affiliation: School of Mathematical and Natural Sciences, University of AR-Monticello, Monticello, AR 71657, USA. mcconnellr@uamont.edu
authors.forename: R M
authors.initials: RM
authors.lastname: McConnell
authors.forename: A W
authors.initials: AW
authors.lastname: Green
authors.forename: C J
authors.initials: CJ
authors.lastname: Trana
authors.forename: M S
authors.initials: MS
authors.lastname: McConnell
authors.forename: J F
authors.initials: JF
authors.lastname: Lindley
authors.forename: K
authors.initials: K
authors.lastname: Sayyar
authors.forename: W E
authors.initials: WE
authors.lastname: Godwin
authors.forename: S E
authors.initials: SE
authors.lastname: Hatfield
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry; D002402:Cathepsin D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004952:Esters / Q000737:chemistry; D005021:Ethylamines / Q000737:chemistry* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D004952:Esters; D005021:Ethylamines; D017320:HIV Protease Inhibitors; D010879:Piperazines; D011480:Protease Inhibitors; D000077489:Piperazine; D016282:Aspartic Acid Endopeptidases; D002402:Cathepsin D