Pyridazine bioisosteres

Giindisch, D., Kampchen, T, Schwarz, S., Seitz, G., Siegl, I, and Wegge, T. 2002. Syntheses and evaluation of pyridazine and pyrimidine containing bioisosteres of ( )-pyrido[3.4-b]homotropane and pyrido-[3.4-b]tropane as novel nAChR ligands. 5 oorgATerf C/2em 10, 1-9. 

Bioisosteric replacement of the chlorop3nr-idinyl moiety in epibatidine with pyridazine generated (136) (Fig. 14.12). Both (136) and its N-methyl derivative (137) maintained much of the potency of natural epibatidine, but the selectivity between and sub-types was enhanced by eight- and 25-fold, respectively. However, the selectivity between... 

A pyridazine-containing bioisostere of (-)-ferruginine was obtained via the coupling of triflate 159 with 4-(tributylstannyl)pyridazine (156) [71]. Several reaction conditions were tried to optimize the yield of this reaction. The best results were obtained using 10 mol% Pd(PhCN)2Cl2, 20 mol% Ph. As. and 20 mol% Cul in combination with three equivalents of LiCI in V-mcthyl pyr roll done. Removal of the carbamate group of 160 finally afforded the bioisostere of (-)-ferruginine (161). 

Most of them showed different activities on the central nervous system. A series of these compounds (Figure 15.15) are acetylcholinesterase inhibitors with variable bioisosteres of the central pyridazine. The replacement by pyridine, 1,2,4-thiadiazole and triazines yields compounds with weaker but stiU acceptable activity. 

Examples from literature show that there are several non-classical bioisosteres for the pyridine system or the pyridazine system. Which is the rationale behind this in order to choose the most appropriate analog to start with An indication could be given by the comparison of the boiling points... 

---