Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (Small Focused Libraries)

Angewandte Chemie - International Edition

Volumn 49, Issue 44, 2010, Pages 8082-8091

  Cooper, Tony W J ^a   Campbell, Ian B ^a   MacDonald, Simon J F ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Compound arrays; Drug discovery; Medicinal chemistry; Small focused libraries; Synthetic methods

Indexed keywords

COMPOUND ARRAYS; DRUG DISCOVERY; MEDICINAL CHEMISTRY; SMALL FOCUSED LIBRARIES; SYNTHETIC METHODS;

OPTIMIZATION;

LIBRARIES;

ORGANIC COMPOUND;

CHEMISTRY; REVIEW;

ORGANIC CHEMICALS;

EID: 78249273274     PISSN: 14337851     EISSN: 15213773     Source Type: Journal    
DOI: 10.1002/anie.201002238     Document Type: Review

References (43)

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7. Log P is the partition coefficient of a compound between octanol and water. Lipophilicity can be calculated and described as clog P (with varying degrees of accuracy), which is a very widely used parameter in medicinal chemistry. ACD labs offer a free clog P calculator http://www.acdlabs.com/ download/logp.html. In a seminal study, Lipinski et al. investigated the lipophilicity of oral drugs (among other compounds) and suggested that for good absorption and permeability (important factors in the discovery of oral drugs) the clogP value should be less than 5
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25. We have encouraged the PhD students and postdoctoral research assistants to apply their new methodology to the preparation of arrays with only partial success. However, when the new methodology has been applied to the preparation of arrays, it has proved a valuable learning experience for the students involved for many of the reasons outlined herein (especially in terms of working with more-polar molecules with more functional groups). The students begin to appreciate the multidisciplinary approach to drug discovery and that working in a team saves much time and effort in comparison to working by themselves. The experience of working in a team, the use of more automated equipment, and their introduction to the concept that in early lead optimization the synthesis of 2 mg of a compound for testing is more important than the overall yield provide the students with an industrial perspective. They also form valuable links with industrial colleagues; these connections should be useful to them in their future careers.
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35. The first report of new methodology carries considerable kudos and usually appears in high-impact journals. Frequently, however, it is sufficient to demonstrate that the methodology works in high yields on a limited range of substrates. Functionality which may interfere with the methodology can be omitted because the novelty factor of the methodology alone is generally sufficient for acceptance by referees. The subsequent demonstration of a refined protocol compatible with a wide range of functionality appears to be valued less, perhaps because it is less novel and less amenable to publication in high-impact journals. The pressure to produce high-impact publications may reduce the incentive for such studies to be carried out. Nonetheless, it is often a subsequent study which indicates the value of the new methodology to the medicinal chemist.
36. The links to the NIH website describing this initiative and the centers are: www.nigms.nih.gov/Initiatives/CMLD; www.nigms. nih.gov/Initiatives/CMLD/ Centers/.
37. Frequently, the synthesis of many monomers and substrates is outsourced.
38. Over this time period, the synthesis of very few arrays was outsourced. We have found it much quicker and logistically much easier for arrays to be made in-house.
39. The medicinal-chemistry team charged with carrying out the lead-optimization process, which results in a clinical candidate, typically comprises (in decreasing order of seniority): a team leader (an experienced medicinal chemist and manager, usually with a PhD), two or three experienced medicinal chemists (graduates with or without a PhD), one or two less experienced graduates, and one or two university students on a one-year placement. All except the team leader carry out synthetic work; all except the students contribute towards the medicinal chemistry commensurate with their grade and experience.
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43. Historically, the majority of reactions were carried out on a less than 10 g scale owing to difficulties in purification; as a result, intermediate availability may have been limited. However (outside of cost constraints or limited commercial availability of the starting materials), intermediate availability is now less of an issue for two reasons: first, the advent of multiple vendors offering the cheap synthesis of bespoke intermediates, and second, the ready availability of purification systems which can readily handle 50-100 g of crude material.