Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library

TY - JOUR

T1 - Lead-oriented synthesis

T2 - Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library

AU - Lüthy, Monique

AU - Wheldon, Mary C.

AU - Haji-Cheteh, Chehasnah

AU - Atobe, Masakazu

AU - Bond, Paul S.

AU - O'Brien, Peter

AU - Hubbard, Roderick E.

AU - Fairlamb, Ian J S

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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 ≤ A log P ≤ 3; (ii) 14 ≤ number of heavy atoms ≤ 26; (iii) total polar surface area ≥ 50 Å2. 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.

AB - 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 ≤ A log P ≤ 3; (ii) 14 ≤ number of heavy atoms ≤ 26; (iii) total polar surface area ≥ 50 Å2. 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.

KW - 3-D shape analysis

KW - Lead-like library

KW - Lead-oriented synthesis

KW - Nitrogen heterocycles

KW - Organolithium-mediated synthesis

UR - http://www.scopus.com/inward/record.url?scp=84937764358&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2015.04.005

DO - 10.1016/j.bmc.2015.04.005

M3 - Article

AN - SCOPUS:84937764358

VL - 23

SP - 2680

EP - 2694

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 11

ER -