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Brown DG, Boström J. Where Do Recent Small Molecule Clinical Development Candidates Come From?. J Med Chem. 2018;61(21):9442-9468doi: 10.1021/acs.jmedchem.8b00675.
Brown, D. G., & Boström, J. (2018). Where Do Recent Small Molecule Clinical Development Candidates Come From?. Journal of medicinal chemistry, 61(21), 9442-9468. https://doi.org/10.1021/acs.jmedchem.8b00675
Brown, Dean G, and Boström, Jonas. "Where Do Recent Small Molecule Clinical Development Candidates Come From?." Journal of medicinal chemistry vol. 61,21 (2018): 9442-9468. doi: https://doi.org/10.1021/acs.jmedchem.8b00675
Brown DG, Boström J. Where Do Recent Small Molecule Clinical Development Candidates Come From?. J Med Chem. 2018 Nov 08;61(21):9442-9468. doi: 10.1021/acs.jmedchem.8b00675. Epub 2018 Jul 09. PMID: 29920198.
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J Med Chem. 2018 Nov 08;61(21):9442-9468. doi: 10.1021/acs.jmedchem.8b00675. Epub 2018 Jul 09.

Where Do Recent Small Molecule Clinical Development Candidates Come From?.

Journal of medicinal chemistry

Dean G Brown, Jonas Boström

Affiliations

  1. Hit Discovery, Discovery Sciences, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States.
  2. Medicinal Chemistry, Cardiovascular, Renal and Metabolism, IMED Biotech Unit , AstraZeneca , Pepparedsleden 1 , Gothenburg SE-431 83 , Sweden.

PMID: 29920198 DOI: 10.1021/acs.jmedchem.8b00675

Abstract

An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.

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