2-(Benzimidazol-2-yl)quinoxalines: a novel class of selective antagonists
at human A(1) and A(3) adenosine receptors designed by 3D database
searching
E. Novellino, B. Cosimelli, M. Ehlardo, G. Greco, M. Iadanza, A. Lavecchia, M. Rimoli, A. Sala, A. Settimo, G. Primofiore, F. Settimo, S. Taliani, C. Motta, K. Klotz, D. Tuscano, M. Trincavelli, and C. Martini. J Med Chem, 48 (26):
8253-60(December 2005)Novellino, Ettore Cosimelli, Barbara Ehlardo, Marina Greco, Giovanni
Iadanza, Manuela Lavecchia, Antonio Rimoli, Maria Grazia Sala, Annalisa
Da Settimo, Antonio Primofiore, Giampaolo Da Settimo, Federico Taliani,
Sabrina La Motta, Concettina Klotz, Karl-Norbert Tuscano, Daniela
Trincavelli, Maria Letizia Martini, Claudia Research Support, Non-U.S.
Gov't United States Journal of medicinal chemistry J Med Chem. 2005
Dec 29;48(26):8253-60..
Abstract
The Cambridge Structural Database (CSD) was searched through two 3D
queries based on substructures shared by well-known antagonists at
the A(1) and A(3) adenosine receptors (ARs). Among the resulting
557 hits found in the CSD, we selected five compounds to purchase,
synthesize, or translate synthetically into analogues better tailored
to interact with the biological targets. Binding experiments using
human ARs showed that four out of five tested compounds turned out
to be antagonists at the A(1)AR or A(3)AR with K(i) values between
50 and 440 nM. Lead optimizations of 2-(benzimidazol-2-yl)quinoxalines
(BIQs, 3) gave the best results in terms of potency and selectivity
at the A(1) and A(3) ARs. Particularly, 2-(4-ethylthiobenzimidazol-2-yl)quinoxaline
(3e) exhibited K(i) values at the A(1)AR, A(2A)AR, and A(3)AR of
0.5, 3440, and 955 nM, respectively, whereas 2-(4-methylbenzimidazol-2-yl)quinoxaline
(3b) displayed at the same ARs K(i) values of 8000, 833, and 26 nM,
respectively.
Novellino, Ettore Cosimelli, Barbara Ehlardo, Marina Greco, Giovanni
Iadanza, Manuela Lavecchia, Antonio Rimoli, Maria Grazia Sala, Annalisa
Da Settimo, Antonio Primofiore, Giampaolo Da Settimo, Federico Taliani,
Sabrina La Motta, Concettina Klotz, Karl-Norbert Tuscano, Daniela
Trincavelli, Maria Letizia Martini, Claudia Research Support, Non-U.S.
Gov't United States Journal of medicinal chemistry J Med Chem. 2005
Dec 29;48(26):8253-60.
%0 Journal Article
%1 Novellino2005
%A Novellino, E.
%A Cosimelli, B.
%A Ehlardo, M.
%A Greco, G.
%A Iadanza, M.
%A Lavecchia, A.
%A Rimoli, M. G.
%A Sala, A.
%A Settimo, A. Da
%A Primofiore, G.
%A Settimo, F. Da
%A Taliani, S.
%A Motta, C. La
%A Klotz, K. N.
%A Tuscano, D.
%A Trincavelli, M. L.
%A Martini, C.
%D 2005
%J J Med Chem
%K & *Databases, A1/*antagonists A2A/metabolism A3/*antagonists Adenosine Adenosine-5'-(N-ethylcarboxamide)/metabolism Adenosine/analogs Animals Benzimidazoles/*chemical Binding, CHO Competitive Cricetinae Design Drug Factual Humans Quinoxalines/*chemical Xanthines/metabolism derivatives/metabolism inhibitors/chemistry/metabolism synthesis/chemistry Receptor Cell
%N 26
%P 8253-60
%T 2-(Benzimidazol-2-yl)quinoxalines: a novel class of selective antagonists
at human A(1) and A(3) adenosine receptors designed by 3D database
searching
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16366607
%V 48
%X The Cambridge Structural Database (CSD) was searched through two 3D
queries based on substructures shared by well-known antagonists at
the A(1) and A(3) adenosine receptors (ARs). Among the resulting
557 hits found in the CSD, we selected five compounds to purchase,
synthesize, or translate synthetically into analogues better tailored
to interact with the biological targets. Binding experiments using
human ARs showed that four out of five tested compounds turned out
to be antagonists at the A(1)AR or A(3)AR with K(i) values between
50 and 440 nM. Lead optimizations of 2-(benzimidazol-2-yl)quinoxalines
(BIQs, 3) gave the best results in terms of potency and selectivity
at the A(1) and A(3) ARs. Particularly, 2-(4-ethylthiobenzimidazol-2-yl)quinoxaline
(3e) exhibited K(i) values at the A(1)AR, A(2A)AR, and A(3)AR of
0.5, 3440, and 955 nM, respectively, whereas 2-(4-methylbenzimidazol-2-yl)quinoxaline
(3b) displayed at the same ARs K(i) values of 8000, 833, and 26 nM,
respectively.
@article{Novellino2005,
abstract = {The Cambridge Structural Database (CSD) was searched through two 3D
queries based on substructures shared by well-known antagonists at
the A(1) and A(3) adenosine receptors (ARs). Among the resulting
557 hits found in the CSD, we selected five compounds to purchase,
synthesize, or translate synthetically into analogues better tailored
to interact with the biological targets. Binding experiments using
human ARs showed that four out of five tested compounds turned out
to be antagonists at the A(1)AR or A(3)AR with K(i) values between
50 and 440 nM. Lead optimizations of 2-(benzimidazol-2-yl)quinoxalines
(BIQs, 3) gave the best results in terms of potency and selectivity
at the A(1) and A(3) ARs. Particularly, 2-(4-ethylthiobenzimidazol-2-yl)quinoxaline
(3e) exhibited K(i) values at the A(1)AR, A(2A)AR, and A(3)AR of
0.5, 3440, and 955 nM, respectively, whereas 2-(4-methylbenzimidazol-2-yl)quinoxaline
(3b) displayed at the same ARs K(i) values of 8000, 833, and 26 nM,
respectively.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Novellino, E. and Cosimelli, B. and Ehlardo, M. and Greco, G. and Iadanza, M. and Lavecchia, A. and Rimoli, M. G. and Sala, A. and Settimo, A. Da and Primofiore, G. and Settimo, F. Da and Taliani, S. and Motta, C. La and Klotz, K. N. and Tuscano, D. and Trincavelli, M. L. and Martini, C.},
biburl = {https://www.bibsonomy.org/bibtex/288d8ab95f13fdfa4344b24f4193c2035/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {d8803dddf24ceb99cab24f33b841258e},
intrahash = {88d8ab95f13fdfa4344b24f4193c2035},
issn = {0022-2623 (Print) 0022-2623 (Linking)},
journal = {J Med Chem},
keywords = {& *Databases, A1/*antagonists A2A/metabolism A3/*antagonists Adenosine Adenosine-5'-(N-ethylcarboxamide)/metabolism Adenosine/analogs Animals Benzimidazoles/*chemical Binding, CHO Competitive Cricetinae Design Drug Factual Humans Quinoxalines/*chemical Xanthines/metabolism derivatives/metabolism inhibitors/chemistry/metabolism synthesis/chemistry Receptor Cell},
month = {Dec 29},
note = {Novellino, Ettore Cosimelli, Barbara Ehlardo, Marina Greco, Giovanni
Iadanza, Manuela Lavecchia, Antonio Rimoli, Maria Grazia Sala, Annalisa
Da Settimo, Antonio Primofiore, Giampaolo Da Settimo, Federico Taliani,
Sabrina La Motta, Concettina Klotz, Karl-Norbert Tuscano, Daniela
Trincavelli, Maria Letizia Martini, Claudia Research Support, Non-U.S.
Gov't United States Journal of medicinal chemistry J Med Chem. 2005
Dec 29;48(26):8253-60.},
number = 26,
pages = {8253-60},
shorttitle = {2-(Benzimidazol-2-yl)quinoxalines: a novel class of selective antagonists
at human A(1) and A(3) adenosine receptors designed by 3D database
searching},
timestamp = {2010-12-14T18:20:40.000+0100},
title = {2-(Benzimidazol-2-yl)quinoxalines: a novel class of selective antagonists
at human A(1) and A(3) adenosine receptors designed by 3D database
searching},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16366607},
volume = 48,
year = 2005
}