Synthesis and Structure–Activity Relationships of Novel Zwitterionic Compounds as Peroxisome Proliferator Activated Receptor α/γ Dual Agonists with Improved Physicochemical Properties

Abstract

We describe herein the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound possessed fatal issues such as potent cytochrome P450 (CYP)3A4 direct inhibitory activity. Thus, we carried out the medicinal optimization to improve these while maintaining the potent PPAR agonistic activity. As a result, the issues were addressed by changing the furan ring to a low lipophilic 1,3,4-oxadiazole ring. Additionally, these oxadiazole derivatives exhibited a significant decrease in plasma glucose and plasma triglyceride levels without marked weight gain.Key words peroxisome proliferator activated receptor; cytochrome P450; drug-drug interactionThe number of people living with diabetes is growing rapidly worldwide. While the number of individuals with diabetes was 151 million in 2002, this number is 366 million at present and is estimated to be 552 million by 2030.1) Of these cases, type 2 diabetes is the majority in both developing and developed countries, whose populations currently account for >90% of all diabetes worldwide.2) In the type 2 diabetic people who show it, insulin resistence poses a cardiovascular risk factor including dyslipidemia, coagulopathy, hypertension and obesity.3) Many drug targets have been investigated to treat type 2 diabetes such as peroxisome proliferator-activated receptor (PPAR), dipeptidyl peptidase IV (DPP-4), glucagonlike peptides-1 (GLP-1), etc. Among these, PPAR is noted as a worthy target to improve metabolic syndrome. PPARs consist of three isoforms, i.e. PPARα, PPARγ and PPARδ, which are members of the superfamily of nuclear transcription factors that include the receptors for steroid, retinoid and thyroid hormones. Activation of PPARγ leads to mitigated insulin resistance by promoting hypertrophied adipocyte differentiation and improving the balance of physiological active substances. 4,5) However their activation has been plagued by adverse effects including weight gain, fluid retention and edema.6) On the other hand, PPARα activation has been identified to mediate the lipid-lowering activity in the study with the fibrate class of hypolipidemic drugs. Furthermore, some PPARα agonists have been reported to reduce weight gain in rodents without an effect on food intake. 7,8) Therefore, PPARα/γ dual agonists are expected to improve blood glucose levels and lipid parameters, together with lowering side effects, i.e. weight gain, caused by PPARγ activation.In the previous report, 9) we obtained zwitterionic compounds showing the PPARα/γ dual agonistic activities. Especially, compound 1 provided highly potent dual activities (α: EC 50 =1.7 nM, γ: EC 50 =4.7 nM, shown in Fig. 1), accompanied by a great glucose lowering effect in the db/db mice. Moreover, it remedied ...

Synthesis and Structure–Activity Relationships of 2-Aminoacetamide Derivatives as Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists

“…We introduced the methyl group at 4-position on the lipophilic tail as a promising substituent in the previous study. 10) As a result, our compound, 22 (Fig. 3), showed good activity and selectivity for PPARα (EC 50 =2.8 nM, ten times stronger than EC 50 =26 nM for PPARγ), which might be preferable to reduce the side effects of PPARγ activation, e.g., weight gain.…”

“…In our previous report, 10) we obtained zwitterionic compounds showing the PPARα/γ dual agonistic activities. In particular, compound 1 provided highly potent dual activities (α: EC 50 =0.55 nM, γ: EC 50 =18 nM, shown in Fig.…”

“…This compound was synthesized by using chloride 18 10) and secondary amine 19 10) in a similar manner to the synthetic approach of compound 15.…”

“…Although the inhibitory activities of 22 for PPARα and PPARγ in the in vitro assay were weaker than those of 1, the physicochemical properties improved 22 showed good in vivo efficacy in the lower dose as compared with 1, which showed the activity at 10 mg/kg. 10) Furthermore, a comparative study of 22 versus Muraglitazar (α: EC 50 =0.3 µM, γ: EC 50 =0.1 µM) 15) was performed in Zucker Fatty rats, which develop type 2 diabetes with obesity, hyperglycemia and hyperinsulinemia. The results are displayed in Table 3.…”

Multitargeted bioactive ligands for PPARs discovered in the last decade

“…Compound 29 in Figure showed more dominant activity for PPARα than for PPARγ with EC 50 s of 2.9 and 33 n m , respectively. The less strong PPARγ activity suggested the decreased side‐effect, such as weight gain mainly induced by PPARγ activation.…”