In order to facilitate the preparation of aminothiazoles

In order to facilitate the preparation of 2-aminothiazoles containing novel D-ring substitutions, a convergent synthetic route was selected which requires the synthesis of common precursor . Straightforward aromatic substitution of 3,4-difluoroacetophenone using 4-methylimidazole provided access to 2-imidazolylacetophenone intermediate in fair yield (). Subsequent acid-catalyzed bromination allowed isolation of the desired bromoacetophenone compound in quantitative yield. The construction of the complementary cyclopentapyrazole fragment toward the synthesis of 2-aminothiazole commenced with the condensation of 2-cyanocyclopentanone with ethylhydrazine in order to afford 3-aminocyclopentapyrazole (). Subsequent reaction of intermediate with benzoyl isothiocyanate furnished benzoyl thiourea in good yield. Isolation of the desired cyclopentapyrazole coupling partner was accomplished following removal of the benzoyl group using KCO. Assembly of the desired final product was then accomplished by Hantzsch condensation of thiourea with bromoethanone to afford aminothiazole in good yield (). This general approach provided access to tetrahydroindazoles –, as well as cyclopentapyrazoles – by selecting the appropriate starting material and utilizing an DMP 777 mg of commercially available substituted hydrazines in the synthetic sequence. A similar synthetic sequence was utilized to isolate the 3--butylpyrazole series of γ-secretase modulators. The condensation of ethylhydrazine with 4,4-dimethyl-3-oxopentanenitrile furnished substituted aminopyrazole (). The subsequent reaction of intermediate with benzoyl isothiocyanate followed by base mediated removal of the benzoyl protecting group provided the desired coupling partner, pyrazolylthiourea , in good overall yield. Finally, reaction between intermediate and common precursor gave the desired aminothiazole (). The use of a convergent synthetic strategy provided access to a large assortment of novel D-ring ligands enabling rapid evaluation of structure–activity relationships within the three related series. In summary, using poorly soluble AGSM as the starting point, a novel series of γ-secretase modulator D-ring analogs possessing a common pyrazole moiety were synthesized leading to the discovery of compounds from three unique families which demonstrate moderate activity for suppressing the formation of Aβ42. Unfortunately, the heterocyclic D-ring derivatives did not provide the anticipated broad increase in compound solubility. Furthermore, the SAR indicated an overall trend in which increasing the lipophilicity of the D-ring leads to improved activity and consequentially reduced aqueous solubility, as well as less than stellar drug-like properties. Despite these challenges, ligands within the 1-substituted 3--butylpyrazole series displayed reasonably good activity and substantially improved properties including aqueous solubility. Rigorous ADME evaluation of the most potent molecule within the family, -ethylpyrazole , revealed an overall good profile with the exception of poor membrane permeability and high plasma protein binding. However, the reasonably good in vivo PK behavior exhibited by pyrazole indicates the need for further development of this scaffold aimed at improving potency, as well as crucial ADME parameters including membrane permeability and aqueous solubility. Based on literature analysis, modulator design has now shifted toward novel B-ring analogs in order to address continuing property related issues and these efforts will be reported in due course. This work was supported by grants from the ; and the Grant . Acknowledgments
Introduction One of the core components of the metabolic syndrome is excess plasma triglycerides (TGs), or hypertriglyceridemia, which is an independent risk factor for coronary heart disease (CHD), above and beyond other insulin resistance-related complications (i.e., high apolipoprotein B [ApoB], low high-density lipoprotein [HDL] cholesterol levels, hypertension, and type 2 diabetes) (Brunzell, 2007, Nordestgaard et al., 2007). This is noteworthy because, despite great strides in the so-called “statin era” to reduce low-density lipoprotein (LDL) cholesterol in high-risk patients, cardiovascular risk remains disproportionately elevated in people with the metabolic syndrome. Unfortunately, hypertriglyceridemia is often not effectively treated, leading to a significant unmet therapeutic need in an increasingly obese population (Brunzell and Ayyobi, 2003).