Journal ArticleDOI
Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists
Ben E. Evans,Kenneth E. Rittle,Mark G. Bock,Robert M. DiPardo,Roger M. Freidinger,W. L. Whitter,George F. Lundell,Daniel F. Veber,Paul S. Anderson,Raymond S.L. Chang,Victor J. Lotti,D. J. Cerino,Tsing-Bau Chen,Paul J. Kling,K. A. Kunkel,James P. Springer,J. Hirshfield +16 more
TLDR
3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.Abstract:
3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.read more
Citations
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The combinatorial synthesis of bicyclic privileged structures or privileged substructures
TL;DR: Privileged substructures are believed to achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns.
Journal ArticleDOI
Natural products: a continuing source of novel drug leads.
Gordon M. Cragg,David J. Newman +1 more
TL;DR: This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases and effective drug development depends on multidisciplinary collaborations.
Journal ArticleDOI
The evolving role of natural products in drug discovery
Frank E. Koehn,Guy T. Carter +1 more
TL;DR: Recent technological advances that help to address issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening and unrealized expectations from current lead-generation strategies have led to a renewed interest in natural products in drug discovery.
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Practical methodologies for the synthesis of indoles.
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Privileged Scaffolds for Library Design and Drug Discovery
TL;DR: This review explores the concept of using privileged scaffolds to identify biologically active compounds through building chemical libraries by revealing through four selected examples the present state of the art in privileged scaffold library synthesis.
References
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Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors
Alessandro Guidotti,Concetta M. Forchetti,M. G. Corda,Dennis Konkel,Carl D. Bennett,Erminio Costa +5 more
TL;DR: DBI injected intraventricularly at doses of 5-10 nmol completely reversed the anticonflict action of diazepam on unpunished drinking and facilitated the shock-induced suppression of drinking by lowering the threshold for this response.
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Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin
Ben E. Evans,Mark G. Bock,Kenneth E. Rittle,Robert M. DiPardo,Willie L. Whitter,Daniel F. Veber,Paul S. Anderson,Roger M. Freidinger +7 more
TL;DR: The design and synthesis of nonpeptidal antagonists of the peptide hormone cholecystokinin are described, and several of these compounds have high specificity and nanomolar binding affinity and are active after oral administration.
Journal ArticleDOI
An opioid benzodiazepine.
Dietmar Römer,Heinz H. Büscher,Ronald C. Hill,R. Maurer,Trevor J. Petcher,H. Zeugner,W. Benson,E. Finner,W. Milkowski,P. W. Thies +9 more
TL;DR: 1-methyl-2(3-thienylcarbonyl)-aminomethyl-5-(2-fluorophenyl)-H-2,3-dihydro-l,4-benzodiazepine (KC5103; tifluadom), acts selectively on opiate κ-receptors.