Dual agonists

More recent studies have confirmed that dual activation of PPARy and PPARo subtypes would be beneficial for treating type-2 diabetes [ 139]. In this connection KRP-297, a TZD derivative has been found to express in vitro as well as in vivo affinity for both the PPARo and PPARy subtypes [152], In light of this, Desai and co-workers have investigated the PPARoj/y dual agonistic activity of a series of TZD and oxazolidinedione derivatives (comp, a. Fig. 22, Table 14) to assess their antidiabetic activity [153,154],... 

Fig. 22 Structures of KRP-297 and thiazolidinedione/oxazolidinedione derivatives associated with PPARa/y dual agonistic activity...

Henke, B. R. Peroxisome proliferator-activated receptor alpha/ gamma dual agonists for the treatment of type 2 diabetes. J. Med. Chem. 2004, 47(17), 4118-4127. 

Kasuga, J., Yamasaki, D., Araya, Y, Nakagawa, A., Makishima, M., Doi, T., Hashimoto, Y, Miyachi, H. Design, synthesis, and evaluation of a novel series of alpha-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha/ delta dual agonists for the treatment of metabolic syndrome. Bioorg. Med. Chem. 2006, 14, 8405-8414. 

Consistent with the rationale for developing PPARa/y dual agonists, combining PPAR8 and PPARy agonist activity could result in a therapy that has the expected benefits on glucose levels with additional positive effects on lipid abnormalities commonly seen in individuals with T2D and the metabolic syndrome. 

Compound 23 is the lead molecule in a series of PPARy/8 dual agonists that is dominant towards PPARy. EC50 values from CTF assays are 4, 19 and 620 nM for human PPARy, PPAR8 and PPARa, respectively [70]. When administered orally to diabetic rats, this compound reduces plasma glucose levels and serum TG by 47% and 51%, respectively, and increases HDL-C by 24%. 

Shi, G.Q., Dropinski, J.F., McKeever, B.M. et al. (2005) Design and synthesis of a-aryloxyphenylacetic add derivatives a novel dass of PPARa/y dual agonists with potent antihyperglycemic and lipid modulating activity. Journal of Medicinal Chemistry, 48, 4457—4468. 

A peroxisome proliferator-activated receptor a/y dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia. Molecular Endocrinology, 19, 1593-1605. 

Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl] methyljglycine [muraglitazar/BMS-298585], a movel peroxisome proliferator-activated receptor a/y dual agonist with efficacious glucose and lipid-lowering activities. Journal of Medicinal Chemistry, 48, 2248-2250. 

Liu, K.G. et al. (2001) Identification of a series of PPARy/8 dual agonists via solid-phase parallel synthesis. Bioorganic 4 Medicinal Chemistry Letters, 11,2959-2962. 

Perlman, S., Costa-Neto, C.M., Miyakawa, A.A., Schambye, H.T., Hjorth, S.A., et al (1997) Dual agonistic and antagonistic property of nonpeptide angiotensin ATI ligands susceptibility to receptor mutations. Mol. Pharmacol. 51 301-311. 

Momose et al. synthesized several thiazolidinediones and oxazoMinediones and evaluated their antidiabetic activities in KK mice. Some of the results are shown in Table 19.9. However, none of the TZDs were superior to rosiglitazone in their profile. In general, most thiazolidinediones have been found to be PPARy agoifists. However, KRP-297 has been reported to be a PPARa and PPARy dual agonist. ... 

Cronet et al." reported a novel PPARa and PPARy dual agonist and cocrystallized 53 (AZ-242) (Scheme 19.17) with PPARy and determined the x-ray stracture. AZ-242 (45) activates PPARa and PPARy, both in vitro and in vivo. In cell-based assay, compound 53 (AZ-242) activated PPARa (EC50, 2.8 jM) and PPARy (EC50, 0.30 J.M), respectively. 

BeUot, M., Galandrin, S., Boularan, C., Matthies, H. J., Despas, F., Denis, C., et al. (2015). Dual agonist occupancy of ATl-R-alpha2C-AR heterodimers results in atypical Gs-PKA signaling. Nature Chemical Biology, ff(4), 271—279. 

Sogawa, Y., Ohyama, T., Maeda, H., Hirahara, K. (2011). Formyl peptide receptor 1 and 2 dual agonist inhibits human neutrophil chemotaxis by the induction of chemoattractant receptor cross-desensitization. JoMr a/ of Pharmacological Sciences, 115(1), 63—68. 

---