Document Detail


Cyclopentane-1,3-dione: a novel isostere for the carboxylic acid functional group. Application to the design of potent thromboxane (A2) receptor antagonists.
MedLine Citation:
PMID:  21863799     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cyclopentane-1,3-diones are known to exhibit pK(a) values typically in the range of carboxylic acids. To explore the potential of the cyclopentane-1,3-dione unit as a carboxylic acid isostere, the physical-chemical properties of representative congeners were examined and compared with similar derivatives bearing carboxylic acid or tetrazole residues. These studies suggest that cyclopentane-1,3-diones may effectively substitute for the carboxylic acid functional group. To demonstrate the use of the cyclopentane-1,3-dione isostere in drug design, derivatives of a known thromboxane A(2) prostanoid (TP) receptor antagonist, 3-(3-(2-(4-chlorophenylsulfonamido)ethyl)phenyl)propanoic acid (12), were synthesized and evaluated in both functional and radioligand-binding assays. A series of mono- and disubstituted cyclopentane-1,3-dione derivatives (41-45) were identified that exhibit nanomolar IC(50) and K(d) values similar to 12. Collectively, these studies demonstrate that the cyclopentane-1,3-dione moiety comprises a novel isostere of the carboxylic acid functional group. Given the combination of the relatively strong acidity, tunable lipophilicity, and versatility of the structure, the cyclopentane-1,3-dione moiety may constitute a valuable addition to the palette of carboxylic acid isosteres.
Authors:
Carlo Ballatore; James H Soper; Francesco Piscitelli; Michael James; Longchuan Huang; Onur Atasoylu; Donna M Huryn; John Q Trojanowski; Virginia M-Y Lee; Kurt R Brunden; Amos B Smith
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-09-09
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  54     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-06     Completed Date:  2011-12-12     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6969-83     Citation Subset:  IM    
Affiliation:
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States. bcarlo@sas.upenn.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Carboxylic Acids / chemistry*
Cyclopentanes / chemical synthesis*,  chemistry,  pharmacology
Drug Design
HEK293 Cells
Humans
Isomerism
Magnetic Resonance Spectroscopy
Mice
Models, Molecular
Quantum Theory
Radioligand Assay
Receptors, Thromboxane A2, Prostaglandin H2 / antagonists & inhibitors*
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Tetrazoles / chemistry
Grant Support
ID/Acronym/Agency:
AG034140/AG/NIA NIH HHS; R01 AG034140/AG/NIA NIH HHS; R01 AG034140-01A2/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Carboxylic Acids; 0/Cyclopentanes; 0/Receptors, Thromboxane A2, Prostaglandin H2; 0/Tetrazoles
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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