Drug Guru

The concept of bioisosterism is central to the Drug Guru project and is fully described in the other chapters of this book. Many of the rules included in the 530 

Conversion of catechols to benzoxazolones is a reported strategy for analoging catechol structures see Blum, G. et al., J. Biol. Chem. 278, 40442—40454 (2003) Ucar, H. et al, Tetrahedron 54, 1763-1772 (1998). 

Conversion to methylenedioxybenzenes is a common strategy for analoging catechol stmctures. For an example of the use of the methylenedioxy strategy in apomorphine analogues in dopamine receptor agonist research, see Balderssarini, R.f., Eur. J. Pharmacol 77, 87-88 (1982). 

Conversion to benzimidazolones is a reported strategy for analoging catechol structures. For examples, see Menichincheri, M. et al.,J. Med. Chem. 47, 6466-6475 (2004). The catechol is compound 2c with IC o 40 pM. The benzimidazolone is compound 4f with IC50 = 19 pM. Note that the benzimidazolone is drawn as a hydroxy tautomer in this paper. 

Conversion to aminobenzothiazoles is a reported strategy for analoging catechol structures. For an example, see Zheng, W. et Med. Chem. 42, TI%1-2294 (1999). The catechol is compound 7, also called TMQ, which has pK, of 7.4 at beta-2 adrenergic receptor. The aminobenzothiazole is compound 9, which has pKj of 6.2. 

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Stewart, K.D., Shiroda, M., and James, C.A. (2006) Drug Guru a computer software program for dmg design using medicinal chemistry rules. Bioorganic ej Medicinal Chemistry, 14, 7011-7022. 

Figure 11.3 Example of Drug Guru input and output. The input structure is dopamine. The 10 output structures resulting from the 10 catechol transformations listed in Table 11.2 are shown...

Number of Drug Guru output structures evaluated 92 62... 

Figure 11.4 Assessment of Drug Guru performance of the Remove -Cl transformation for reducing hERG affinity (dofetilide displacement assay) using a matched molecular pair analysis of 151 compound pairs.

Summary The Abbott Experience with the Drug Guru Project 1197... 

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