Bioisosterism lead optimization

P.H. Olesen, The use of bioisosteric groups in lead optimization, Curr. Opin. Drug Disc. Dev. 4 (2001) 471-478. 

Figure 8.8 Classical and non-classical bioisosteres (Reprinted with permission from, Showell, G.A., Mills, J.S. Chemistry challenges in lead optimization Silicon isosteres in drug discovery. Drug Discov. Today, 8, 551-556, copyright 2003, Elsevier.)...

This chapter provides an overview of the history of bioisosterism from its begiim-ing in the early twentieth century to the present day. We also provide an overview of the importance of judicious bioisosteric replacement in lead optimization to assist in the path toward a viable clinical candidate and, ultimately, a drug. 

These four key generalized parameters, with specific properties governing the optimization of each, provide what can be formalized as the changes that may be made in lead optimization to provide guidance on the optimization of functional groups that are bioisosteric. 

Burger s definition succinctly defines bioisosteres including aH of the aforementioned extensions defined by other scientists in the field. The next section focuses on the specific improvements in lead optimization that can be gained by prudent application of the concepts of bioisosterism. 

AP, that result from the application of particular transformations, AS, and hence provide an inverse quantitative structure-activity relationship (QSAR) approach to lead optimization [19]. Another difference is that, given an appropriate source of data, they can model not only biological activity, the principal focus of the bioisosterism approaches, but also any chemical, physicochemical, or ADMETproperty that needs to be optimized. 

The design and application of bioisosteres in drug discovery has been and will continue to be an important approach to structural modification as medicinal chemists address the wide range of problems that are encountered in contemporary lead optimization initiatives. 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Andersen, K. E., Sprensen, J. L Huusfeldt, P. 0., Knutsen, L. J., Lau, J., Lundt, B. F., et al. (1999) Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates../. Med. Chem. 42,4281 4291. 

Successful development of a drug, from choice of the lead structure through preparation and testing of derivatives and bioisosteres to selection of the clinical candidate, requires that properties be optimized for potency, selectivity and delivery. 

Anzali, S., Barnickel, G., Krug, M., Wagener, M. and Gasteiger, J. (1997) Kohonen neural network a novel approach to search for bioisosteric groups, in Computer-Assisted Lead Finding and Optimization... 

Langdon, S.R., Ertl, P., and Brown, N. (2010) Bioisosteric replacement and scaffold hopping in lead generation and optimization. Molecular Informatics, 29, 366-385. 

Bioisosteric replacement and scaffold hopping in lead generation and optimization. Molecular Informatics,... 

Whereas some reviews on bioisosteres are found in the literature, as well as chapters in medicinal chemistry books, no dedicated monograph on bioisosteres has been published so far. Thus, we are very grateful to Nathan Brown for editing such a book, which will help novices in the field as well as experienced scientists to manage lead structure optimization in an even more rational manner. In addition, we are... 

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