title: A paradigm for drug discovery employing encoded combinatorial libraries.
abstract: Very large combinatorial libraries of small molecules on solid supports can now be synthesized and each library element can be identified after synthesis by using chemical tags. These tag-encoded libraries are potentially useful in drug discovery, and, to test this utility directly, we have targeted carbonic anhydrase (carbonate dehydratase; carbonate hydro-lyase, EC 4.2.1.1) as a model. Two libraries consisting of a total of 7870 members were synthesized, and structure-activity relationships based on the structures predicted by the tags were derived. Subsequently, an active representative of each library was resynthesized (2-[N-(4-sulfamoylbenzoyl)-4'-aminocyclohexanespiro]-4-oxo-7 -hydroxy- 2,3-dihydrobenzopyran and [N-(4-sulfamoylbenzoyl)-L-leucyl]piperidine-3-carboxylic acid) and these compounds were shown to have nanomolar dissociation constants (15 and 4 nM, respectively). In addition, a focused sublibrary of 217 sulfamoylbenzamides was synthesized and revealed a clear, testable structure-activity relationship describing isozyme-selective carbonic anhydrase inhibitors.
authors.affiliation: Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Burbaum
authors.forename: M H
authors.initials: MH
authors.lastname: Ohlmeyer
authors.forename: J C
authors.initials: JC
authors.lastname: Reader
authors.forename: I
authors.initials: I
authors.lastname: Henderson
authors.forename: L W
authors.initials: LW
authors.lastname: Dillard
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.forename: T L
authors.initials: TL
authors.lastname: Randle
authors.forename: N H
authors.initials: NH
authors.lastname: Sigal
authors.forename: D
authors.initials: D
authors.lastname: Chelsky
authors.forename: J J
authors.initials: JJ
authors.lastname: Baldwin
mesh_terms: D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016208:Databases, Factual; D015195:Drug Design; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010600:Pharmacology / Q000379:methods*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C094323:(N-(4-sulfamoylbenzoyl)leucyl)piperidine-3-carboxylic acid; C094322:2-(N-(4-sulfamoylbenzoyl)-4'-aminocyclohexanespiro)-4-oxo-7-hydroxy-2,3-dihydrobenzopyran; D001578:Benzopyrans; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D010880:Piperidines; D013141:Spiro Compounds; D007930:Leucine