br Medium to long chain fatty

Medium- to long-chain fatty acids Medium- to long-chain fatty acids impart a wide range of physiological effects. Medium-chain and long-chain fatty acids have 6–12 carbons and >12 carbons, respectively. As the energy source, these fatty acids are supplied primarily by food intake, biosynthesis, and lipolysis from adipose tissues. However, as unsaturated fatty acids such as linoleic acid, linolenic acid, and DHA that have more than 2 double bonds in the structures were not provided by biosynthesis in humans, we need to derive these macromolecules from food. Medium- to long-chain fatty acids are metabolized by β-oxidation and used as an energy source in various tissues. On the other hand, fatty Amidepsine A receptors that are activated by these fatty acids provided the novel possibility of the biological functions of fatty acids for signaling molecules and the insight for the importance of dietary habits.
Medium- to long-chain fatty acid receptors
Conclusion
Introduction Type 2 diabetes mellitus (T2DM) is a prevalent metabolic syndrome with insufficient insulin secretion and/or insulin resistance [1], [2]. Many insulin secretagogues (e.g. sulfonylureas) are commonly prescribed for the administration of T2DM [3]. However, sulfonylureas are often associated with the side effect of hypoglycemia [4]. Novel insulin secretagogues with low risk of hypoglycemia and preferable glycemic control are thus desirable. Currently, the free fatty acid receptor 1 (FFA1) has emerged as a promising anti-diabetic target [5]. FFA1 is mainly expressed in pancreas where it stimulates glucose-dependent insulin secretion, providing a huge advantage of decreasing the risk of hypoglycemia compared to sulfonylureas [6], [7], [8]. Moreover, the limited tissue distribution of FFA1 reduces the possibility of “on-target” side effects in other tissues [9]. As collected in our previous review [10], a series of synthetic agonists have been developed in different phase (Fig. 1) [11], [12], [13], [14], [15], [16], [17], [18]. Among them, the candidates TAK-875, LY2881835, and AMG-837 have reached clinical trials as anti-diabetic agents [5], [10]. Besides, the potential chemical space of FFA1 agonists has also been systematically explored in our laboratory [19], [20], [21], [22], [23], [24], [25]. Herein, the Takeda’s compound 1 (Fig. 1) was selected as the lead compound, because its high potency and simple structure to avoid hypertrophied molecular size in the process of structure modifications. However, compound 1 has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to β-oxidation [11]. As summarized in Fig. 2, the pathway of β-oxidation is derive from the cinnamic acid 2 and ultimately afford the benzoic acid 3 [11], [26], and the metabolic pathway can be blocked by classic structural modifications such as α- and/or β-disubstitution [27]. Therefore, we tried to decrease the generation of cinnamic acid 2 by incorporating two deuterium atoms at the α-position of phenylpropionic acid (e.g., compound 4), because the kinetic isotope effect of deuterium at sites of metabolism is the rate determining step can reduce metabolism [28], [29], [30]. After systematic exploration of structure-activity relationship (SAR) in deuterated series, the compound 18 was identified as an orally bioavailable agonist with robust glucose-lowering effect in mice. As expected, the β-oxidation of phenylpropanoic acid has been interrupted in the deuterated analog 18, resulting in superior PK profiles than compound 1. Moreover, the risk of hypoglycemia of compound 18 was also evaluated in rodent models.
Results and discussion
Conclusion Aiming to improve PK properties of compound 1 against β-oxidation, the design strategy of incorporating two deuterium atoms at the α-position of phenylpropionic acid was developed to block the initial dehydrogenation reaction of β-oxidation. Indeed, the preferred compound 18 revealed superior PK profiles, especially with respect to half-life and plasma exposure, which was consistent with the reduced β-oxidation. Moreover, the glucose level was significantly suppressed in compound 18-treated group, and the AUC0−90min of blood glucose was slightly lower than that of TAK-875. Different from glibenclamide, no side effect of hypoglycemia was observed in rats after administrating compound 18 (40 mg/kg). Therefore, compound 18 will be a promising candidate, and provided a lot of useful information for us to develop deuterated analogs and design more competitive FFA1 agonists.