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The syntheses of some erythro-and threo-9-(2-hydroxy-3-alkyl)adenines from 5-amino-4,6-dichloropyrimidine and the appropriate amino alcohols are described. Based on earlier studies, it was predicted and substantiated that the erythro diastereoisomers would be more potent inhibitors of adenosine deaminase than their corresponding threo diastereoisomers. These data support the concept that on adenosine deaminase there is a single binding site for the adenine moiety of the inhibitors and that there is a close spatial relationship of the methyl binding site, the hydroxyl binding site, and the large hydrophobic region utilized by the 9 substituent of the inhibitors.Earlier studies have shown that calf intestinal mucosal adenosine deaminase possesses several regions which are important for binding the 9 substituent of various 9-substituted adenines.1"3 These binding areas for the 9 substituent are a large hydrophobic region,1 a hydroxyl binding site,2 and a specific methyl binding region.3 Furthermore, it has been demonstrated that when the 9 substituent of some 9-substituted adenines contains a chiral center, there is a stereoselectivity in the formation of the enzyme-inhibitor complex.3•4 For example, with some 9-( 1hydroxy-2-alkyl)adenines, the preferred chiral center for El complex formation has the R configuration4 whereas with 9-(2-hydroxypropyl)adenine, the chiral center with the S' configuration is bound more tightly to the enzyme than the compound with R configuration.3 With this insight into the types of binding regions and the stereoselectivity of inhibition of adenosine deaminase at two different chiral centers of some 9-substituted adenines, it should be possible to design potent inhibitors of this enzyme. This paper describes the syntheses of some 9-(2hydroxy-3-alkyl)adenines and their evaluation as inhibitors of adenosine deaminase.

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A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.

A series of 48 steroids has been studied with the SYBYL QSAR module using Relative Binding Affinities (RBAs) to progesterone and androgen receptors obtained from the literature. Models for the progesterone and androgen data were developed. Both models show regions where sterics and electrostatics correlate to binding affinity but are different for androgen and progesterone which suggests differences possibly important for receptor selectivity. The progesterone model is more predictive than the androgen (predictive r2 of 0.725 vs. 0.545 for progesterone and androgen, respectively).

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