A paradigm for drug discovery employing encoded combinatorial libraries.
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.
Burbaum
J J
JJ
Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
Ohlmeyer
M H
MH
Reader
J C
JC
Henderson
I
I
Dillard
L W
LW
Li
G
G
Randle
T L
TL
Sigal
N H
NH
Chelsky
D
D
Baldwin
J J
JJ
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
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