Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library.
Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc α-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) -1⩽AlogP⩽3; (ii) 14⩽number of heavy atoms⩽26; (iii) total polar surface area⩾50Å(2). The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under-represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space.
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
Monique
M
Lüthy
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
Mary C
MC
Wheldon
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
Chehasnah
C
Haji-Cheteh
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK; Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
Masakazu
M
Atobe
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
Paul S
PS
Bond
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK. Electronic address: peter.obrien@york.ac.uk.
Peter
P
O'Brien
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK; Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.
Roderick E
RE
Hubbard
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
Ian J S
IJ
Fairlamb
D020650:Combinatorial Chemistry Techniques / Q000379:methods; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D008094:Lithium / Q000737:chemistry*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis*; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis*
D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D010879:Piperazines; D010880:Piperidines; D011759:Pyrrolidines; D054852:Small Molecule Libraries; D000077489:Piperazine; C032727:piperidine; D008094:Lithium; C032519:pyrrolidine
3-D shape analysis; Lead-like library; Lead-oriented synthesis; Nitrogen heterocycles; Organolithium-mediated synthesis