title: Design and synthesis of a focused library of novel aryl- and heteroaryl-ketopiperazides.
abstract: 1-Phenyl-4-piperazinyl-carbonyl-substituted nitrogen-containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D-24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identified. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties. Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization.
authors.affiliation: Drug Discovery, Zentaris GmbH, Frankfurt am Main, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gerlach
authors.forename: Eckhard
authors.initials: E
authors.lastname: Claus
authors.forename: Silke
authors.initials: S
authors.lastname: Baasner
authors.forename: Gilbert
authors.initials: G
authors.lastname: Müller
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Polymeropoulos
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidt
authors.forename: Eckhard
authors.initials: E
authors.lastname: Günther
authors.forename: Jürgen
authors.initials: J
authors.lastname: Engel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D014404:Tubulin; D003078:Colchicine