Towards the realisation of lead-oriented synthesis.

Sourcing large numbers of lead-like molecules - compounds that would serve as good starting points for drug discovery programmes - is currently very challenging. The concept of lead-oriented synthesis has recently been articulated to capture the specific problem of preparing diverse small molecules with lead-like molecular properties. In this Feature, some methods that might be used to prepare lead-like molecular scaffolds are described, and presented in the context of diversity-oriented synthetic strategies that allow wide variation in molecular scaffold. It is concluded that the development of a wider toolkit of reactions that is reliable with more polar substrates will be required to allow genuine combination of molecular scaffold within lead-like chemical space.

[1]  John P Wolfe,et al.  New strategy for the synthesis of substituted morpholines. , 2009, The Journal of organic chemistry.

[2]  Channa K. Hattotuwagama,et al.  Lead-oriented synthesis: a new opportunity for synthetic chemistry. , 2012, Angewandte Chemie.

[3]  Giovanni Muncipinto,et al.  Short synthesis of skeletally and stereochemically diverse small molecules by coupling petasis condensation reactions to cyclization reactions. , 2006, Angewandte Chemie.

[4]  Stuart L Schreiber,et al.  Towards the optimal screening collection: a synthesis strategy. , 2008, Angewandte Chemie.

[5]  Spiros Liras,et al.  An efficient synthesis of bridged heterocycles from an Ir(I) bis-amination/ring-closing metathesis sequence. , 2012, Organic letters.

[6]  P. Clemons,et al.  Route to three-dimensional fragments using diversity-oriented synthesis , 2011, Proceedings of the National Academy of Sciences.

[7]  Artis Klapars,et al.  Synthesis of medium ring nitrogen heterocycles via a tandem copper-catalyzed C-N bond formation-ring-expansion process. , 2004, Journal of the American Chemical Society.

[8]  Allan M Jordan,et al.  The medicinal chemist's toolbox: an analysis of reactions used in the pursuit of drug candidates. , 2011, Journal of medicinal chemistry.

[9]  Francesco Marchetti,et al.  Towards the systematic exploration of chemical space. , 2012, Organic & biomolecular chemistry.

[10]  T. Ritchie,et al.  The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design? , 2009, Drug discovery today.

[11]  Adam Nelson,et al.  Convergent, regiospecific synthesis of quinolines from o-aminophenylboronates. , 2008, Organic letters.

[12]  Danielle M. Schultz,et al.  Palladium-catalyzed alkene carboamination reactions for the synthesis of substituted piperazines. , 2009, Tetrahedron.

[13]  David R Spring,et al.  Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. , 2010, Nature communications.

[14]  C. Humblet,et al.  Escape from flatland: increasing saturation as an approach to improving clinical success. , 2009, Journal of medicinal chemistry.

[15]  Stuart L Schreiber,et al.  A synthesis strategy yielding skeletally diverse small molecules combinatorially. , 2004, Journal of the American Chemical Society.

[16]  Alan Rolfe,et al.  Formal [4+3] epoxide cascade reaction via a complementary ambiphilic pairing strategy. , 2010, Organic letters.

[17]  P. Leeson,et al.  A comparison of physiochemical property profiles of development and marketed oral drugs. , 2003, Journal of medicinal chemistry.

[18]  J. Wolfe,et al.  Selective synthesis of 5- or 6-aryl octahydrocyclopenta[b]pyrroles from a common precursor through control of competing pathways in a Pd-catalyzed reaction. , 2005, Journal of the American Chemical Society.

[19]  John P Wolfe,et al.  Mild conditions for the synthesis of functionalized pyrrolidines via Pd-catalyzed carboamination reactions. , 2007, Organic letters.

[20]  György M. Keserü,et al.  The influence of lead discovery strategies on the properties of drug candidates , 2009, Nature Reviews Drug Discovery.

[21]  Adam Nelson,et al.  Synthesis of small molecules with high scaffold diversity: exploitation of metathesis cascades in combination with inter- and intramolecular Diels-Alder reactions. , 2010, Chemistry.

[22]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[23]  Nathan T. Ross,et al.  An aldol-based build/couple/pair strategy for the synthesis of medium- and large-sized rings: discovery of macrocyclic histone deacetylase inhibitors. , 2010, Journal of the American Chemical Society.

[24]  Anang A Shelat,et al.  Scaffold composition and biological relevance of screening libraries. , 2007, Nature chemical biology.

[25]  Giovanni Muncipinto,et al.  Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries. , 2012, The Journal of organic chemistry.

[26]  Stuart L Schreiber,et al.  A planning strategy for diversity-oriented synthesis. , 2004, Angewandte Chemie.

[27]  J. Wolfe,et al.  Mild conditions for Pd-catalyzed carboamination of N-protected hex-4-enylamines and 1-, 3-, and 4-substituted pent-4-enylamines. Scope, limitations, and mechanism of pyrrolidine formation. , 2008, The Journal of organic chemistry.

[28]  Tudor I. Oprea,et al.  Is There a Difference between Leads and Drugs? A Historical Perspective , 2001, J. Chem. Inf. Comput. Sci..

[29]  William Lewis,et al.  Synthesis of natural-product-like scaffolds in unprecedented efficiency via a 12-fold branching pathway , 2011 .

[30]  Didier Rognan,et al.  Assessing the Scaffold Diversity of Screening Libraries , 2006, J. Chem. Inf. Model..

[31]  Simon J F Macdonald,et al.  Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focused libraries). , 2010, Angewandte Chemie.

[32]  Hanno Wild,et al.  The importance of chemistry for the future of the pharma industry. , 2011, Angewandte Chemie.

[33]  Adam Nelson,et al.  A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds. , 2013, Chemical communications.

[34]  Danielle M Schultz,et al.  Intramolecular alkene carboamination reactions for the synthesis of enantiomerically enriched tropane derivatives. , 2011, Organic letters.

[35]  Stuart L Schreiber,et al.  Skeletal diversity via a folding pathway: synthesis of indole alkaloid-like skeletons. , 2005, Organic letters.

[36]  Charles C. Persinger,et al.  How to improve R&D productivity: the pharmaceutical industry's grand challenge , 2010, Nature Reviews Drug Discovery.

[37]  Adam Nelson,et al.  Synthesis of Natural-Product-Like Molecules with Over Eighty Distinct Scaffolds** , 2008, Angewandte Chemie.

[38]  Adam Nelson,et al.  Convergent synthesis of dihydroquinolones from o-aminoarylboronates , 2009 .

[39]  Jingyao Zhou,et al.  Multicomponent approach in the synthesis of 2,2,6-trisubstituted morpholine derivatives. , 2012, Organic letters.

[40]  A. H. Lipkus,et al.  Structural Diversity of Organic Chemistry. a Scaffold Analysis of the Cas Registry , 2022 .