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Due to the highly basic nature of the guanidine group, guanidine- containing compounds usually display poor oral bioavailabilities in vivo. Attaching electron-withdrawing groups such as cyano, nitro, acyl or sulfonyl to the nitrogen atom to attenuate the basicity of guanidine is one of the most classical techniques used in medicinal chemistry. Recently, another novel bioisosteric replacement of the guanidine group with an amidinohydrazone motif was reported in the search for direct antithrombins with good pharmacokinetic properties (24). Although compound 21 and its related series of analogs exhibited potent and selective inhibition of thrombin, in vivo evaluation was limited by its poor solubility. Amidinohydrazone replacement of the guanidine moiety resulted in compound 22, which is slightly more potent than compound 21 in vitro. More importantly, compound 22 showed good bioavailability and long half-life in rabbits and dogs, respectively.

Phenol - In the search for more potent and selective dopamine (DA) D2 agonists for their implication in several psychiatric and neurological illnesses such as schizophrenia, Parkinson's disease and drug addiction, Mewshaw and coworkers published a series of modifications centered around the bioisosteric replacement of the metabolically labile 3-OH-phenol moiety in 23 with the aim of improving the oral bioavailability of this class of compounds (25). The bioisosteric analogs, such as indole 24, indolone 25, 2-trifluoromethyl-benzimidazole 26, and benzimidazol-2-one 27, were observed to have excellent affinity for the D2 receptor. Compounds 24 and 27 also demonstrated in vivo efficacy when administered both orally and subcutaneously.

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The alkylsulfonamide group is commonly used as a bioisosteric replacement for the phenol group as it has similar pKa values to that of the phenolic hydroxy group. As demonstrated in a recent publication on the lead optimization of a gonadotropin releasing hormone (GnRH) antagonist, methylsulfonamide replacement of the phenol in 28 resulted in compound 29, with a 4-fold increase in binding affinity compared to 28 (26).

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