Methods for Drug Discovery: Development of Potent, Selective, Orally Effective Cholecystokinin Antagonists

Evans, B. E. et al.

J. Med. Chem. 1988, 31, 2235-2246.

A privileged structure "is a single molecular framework able to provide ligands for diverse receptors..."

"...judicious modification of such structures could be a viable alternative in the search for new receptor agonists and antagonists."

Peptidomimetic Regulation of Growth Hormone Secretion

Patchett et al.

Endocrine Rev. 1997, 18, 621-645.

"The term "privileged structures" refers to structural units that are found on a recurring basis in receptor ligands. Their recognition and derivatization have been proposed as a useful way to prepare receptor agonists and antagonists."

Spiroindanylpiperidine-privileged structure

New 4-point pharmacophore method for molecular similarity and diversity applications: overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures

Mason, J. S.; Morize, I.; Menard, P. R.; Cheney, D. L.; Hulme, C.; Labaudiniere, R. F.

J. Med. Chem. 1999, 42, 3251-3264.

"The "privileged" substructure concept for the design of high-affinity ligands is presented, and an example of this new method is described..."

Biphenyltetrazole, spiroindanylpiperidine,

indole, benzylpiperidine as privileged structures

 

Glossary of Terms Used in Combinatorial Chemistry

IUPAC, Pure Appl. Chem. 1999, 71, 2349-2365.

"Privileged Structure: Substructural feature which confers desirable (often drug-like) properties on compounds containing that feature. Often consists of a semi-rigid scaffold which is able to present multiple hydrophobic residues without undergoing hydrophobic collapse, e.g. diazepam in which the diphenylmethane moiety prevents association of the aromatic rings."

Privileged Structures-An Update

Patchett, A. A.; Nargund, R. P.

Ann. Rep. Med. Chem. 2000, 35, 289-298.

The term "peptidyl privileged structures" was introduced by A. Patchett et al. to describe "a design in which a privileged structure anchor is derivatized with dipeptides or capped amino acids."

- "Privileged structures for GPCRs"

- "Peptidyl privileged structures"

Natural Product-like Combinatorial Libraries Based on Privileged Structures

Nicolaou, K. C. et al.

J. Am. Chem. Soc. 2000, 122, 9939-9953.

"We now introduce a strategy for the construction of natural product-like libraries using the concept of privileged structures, a term first proposed by Evan et al. to describe select structural types (originally benzodiazepines and benzazepines) that bind to multiple, unrelated classes of protein receptors as high affinity ligands. These privileged structures are tipically rigid, polycyclic heteroatomic systems capable of orienting varied substituent patterns in a well-defined three-dimensional space."

Exploring privileged structures: the combinatorial synthesis of cyclic peptides

Smythe, M. L. et al.

J. Comput. Aided Mol. Des. 2002, 16, 415-430.

Review

Exploring privileged structures: the combinatorial synthesis of cyclic peptides

Smythe, M. L. et al.

Mol. Divers. 2002, 5, 289-304.

Review: macrocyclic cyclic peptides and cyclic dipeptides or diketopiperazines as privileged structures

The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Structures

Smythe, M. L. et al.

Chem. Rev. 2003, 103, 893-930.

"The privileged structure term has gained prominence in the literature since it was first introduced some 15 years ago. However, by definition privileged structures are not structures in their own right, as they usually comprise only a subsection of any molecule. For clarification in this review, we have instead used the term privileged substructure, which is aligned with the common practice of describing a component of a molecule."

Review

Smythe's Classification:

- Phenyl-Substituted Monocycles

- Fused (7-6) Ring Systems

- Fused (6-6) Ring Systems

- Fused (5-6) Ring Systems

Privileged Structure-Based Combinatorial Libraries Targeting G Protein-Coupled Receptors ( GPCRs)

Assay Drug Dev. Technol. 2003, 1, 579-592.

Tao Guo and Doug W. Hobbs

Pharmacopeia, Inc., Princeton, NJ

"Privileged structures, with their inherent affinity for diverse biological receptors, represent an ideal source of core scaffolds and capping fragments for the design and synthesis of combinatorial libraries targeted at various receptors."

Medicinal chemistry of target family-directed masterkeys

Müller, G.

Drug Discov. Today, 2003, 8, 681-691.

"Privileged structures: room for interpretation

The term "privileged structure" has appeared more frequently in the literature over the past few years and a refined definition might help to distinguish more clearly between recurring strutural elements that elicit false positive responses in biological assays, so-called privileged structures that lack a strict target class relation, and privileged structure that address a protein family wide commonality in terms of the involved molecular recognition phenomenon."

Privileged Structures: Applications in Drug Discovery

R.W. DeSimone, K.S. Currie, S.A. Mitchell, J.W. Darrow and D.A. Pippin

Comb. Chem. High Throughput Screen. 2004, 7, 473-493.

" Privileged structures are molecular scaffolds with versatile binding properties, such that a single scaffold is able to provide potent and selective ligands for a range of different biological targets through modification of functional groups. In addition, privileged structures typically exhibit good drug-like properties, which in turn leads to more drug-like compound libraries and leads. "

Review

www.bentham.org/cchts/cchts7-5.htm#link8

www.ncbi.nlm.nih.gov/...15320713

Recognition of privileged structures by G-protein coupled receptors

Bondensgaard, K.; Ankersen, M.; Thogersen, H.; Hansen, B. S.; Wulff, B. S.; Bywater, R. P.

J. Med. Chem. 2004, 47, 888-899.

" Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. "

www.ncbi.nlm.nih.gov/entrez/...Abstract

Drews Offers Bleak Outlook for Drug Development

March 2004

" Juergen Drews then offered a few lifelines for the industry, including "privileged structures," a concept that he says was developed as early as 1988 and is now being revisited from a target perspective. A privileged structure refers to the idea that one type of structure might be responsible for a multitude of biological effects. "It somehow corresponds to the idea that there is some evolutionary convergence of structures," Drews said. "

www.biosciencetechnology.com/ShowPR~PUBCODE~09....html

Development of Privileged Structure Based Libraries

Jacob Ravn

PhD defence, october 2004

The Danish University of Pharmaceutical Sciences

The term " privileged structure " was first introduced in 1988. A privileged structure was defined as "a single molecular framework able to provide ligands for diverse receptors."

indoles, aryl piperazines, spiro phenylpiperidines, biphenyls, benzopyranes and 1,4-dihydropyridines

www.dfuni.dk/phd/defences/jacobravn.htm

Exploitation of silicon medicinal chemistry in drug discovery

Mills JS, Showell GA.

Expert Opin. Investig. Drugs, 2004, 13, 1149-1157.

" The application of organosilicon medicinal chemistry in the context of privileged structures to aid drug design and development is one such innovative approach that is reviewed in this paper."

www.ncbi.nlm.nih.gov/...15330746

Structural bioinformatics meets rational drug design

Müller, G.; Oss N. L.

" Consequently, these so-called privileged structures provide versatile templates for a subsequent modular decoration to confer the desired target specificity within a particular protein family. "

" The ultimate goal of the privileged structureapproach is to derive generic rules that govern the design of ligand mimetics from a thorough analysis of a protein-superfamily, thus not only allowing for a rapid functional elucidation of a putative target protein, but also probing the accessibility of a potentialdisease target by low-molecular weight compounds. "

www2.chemie.uni-erlangen.de/external/cic/....pdf