Strategic MedChem Reagents for a Judicial Design of Focused Compound Arrays

Authors: Andrea Altieiri PhD, Prof. Alexander V. Kurkin & Dmitry S. Belov PhD, Evgeny R. Lukyanenko and Ivan A. Andreev– EDASA Scientific srls- via Stingi 37 – 66050 San Salvo (CH) -  Italy www.edasascientific.com

Since the advent of combinatorial chemistry, the scientific community has intensively screened compounds for biological purposes. As combinatorial chemistry has matured the scientific community has gained a better understanding of the drug-like properties of molecules. This, in combination with better computational and biological tools, has led to significant progress in the design and creation of new compound libraries (IP improvement, Drug-like orientated, Lead-like orientated, Focused, BIOS, PPI, 3D-mentionality, Diversity, etc). This progress is well reflected in the chemical complexity of recent commercial compound libraries (Med. Chem. Commun., 2012, 3, 571- Organic chemistry: Molecular diversity by design - Nature 457, 153-154, 2009 doi:10.1038/457153a; Stuart L. Schreiber; Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules - Warren R.J.D. Galloway, Albert Isidro-Llobet & David R. Spring; Biology-inspired synthesis of compound libraries - Cell. Mol. Life Sci. 65 (2008) 1186 – 1201; M. Kaisera , S. Wetzelb, c, K. Kumarb, c and H. Waldman ). However, in order to reach such a high degree of chemical complexity, a lot of resources and several synthetic steps have been required, all the more so because, in most cases, no “ad-hoc” starting reagents have been available.

Thus, even though modern compound libraries are more attractive and lead to better hit rates, they are less attractive from the economic point of view and even large pharmaceutical companies may have some difficulty in carrying out R&D in this direction. Moreover, on top of the initial investment, in the lucky event of a hit, its chemistry follow up will be again affected by the hit’s chemistry complexity, with additional expenses in the lead optimization program.

It is not uncommon for a medicinal chemist to have to drop the initial drug design project for a similar and more pragmatic analogue of its target molecule due to a lack of a proper reagent or starting material.  These “pragmatic adjustments” often lead to the generation of well-known fragments with an obvious deleterious effect on the novelty and drug-like property of the “pragmatically adjusted compound”.