Synthesis and Evaluation of Novel Phenylethanolamine Derivatives containing Acetanilides as Potent and Selective .BETA.3-Adrenergic Receptor Agonists

Abstract

A major increase in the prevalence of obesity and non-insulin dependent (type II) diabetes and related cardiovascular disorders has led to the search for new pharmacological approaches in the treatment of these conditions. 1,2) In the early 1980s, the b3-adrenergic receptor (AR) was identified as a possible therapeutic target for the treatment of type II diabetes and obesity. 3,4) Early potent and selective b3-AR agonists, such as BRL-37344 5) and CL-316243, 6) were reported to be effective anti-obesity and anti-diabetic agents in rodents (Fig. 1). 7) Human clinical trials with these agents for the treatment of metabolic disorders, however, have been disappointing due to a lack of efficacy or an unfavorable sideeffect profile. 8,9) The clinical failure of such compounds has been attributed to a lack of sufficient b3-AR potency and selectivity relative to b1-and b2-ARs resulting from pharmacologic differences between rodent and human receptors, which was supported by the discovery, cloning, and characterization of the human, rat, and mouse b3-ARs. 10-12) Recent studies indicated that, in addition to adipocytes, the b3-AR is also distributed in human urinary bladder detrusor tissue and its relaxation occurs mainly via b3-AR. [13][14][15] The availability of appropriate human receptors has given rise to the design and synthesis of a new generation of b3-AR agonists with high potency. Subtype selectivity for b3-AR agonists must be kept specifically in mind, since activation of the b1-or b2-ARs would cause undesirable side effects such as increased heart rate or muscle tremors.We previously described efforts in this area, including the disclosure of acetanilide analogues exemplified by 2-pyridylacetanilide 1, which showed potent b3-AR agonistic activity with modest functional selectivity over b1-AR and oral hypoglycemic activity in diabetic kk mice (Fig. 2). 16) Compound 1 was found, however, to exhibit poor bioavailability in rats (Fϭ2%), probably due to the rapid metabolism of the 4-hydroxyphenoxy moiety on the left-hand side. Many kinds of phenylethanolamine-based b3-AR agonists have been reported (Fig. 3) 4,17) and we therefore decided to explore the alternative structures to the 4-hydroxyphenoxymethyl moiety. Subsequently, we attempted to modify the central part and the pyridyl moiety on the right-hand side (Fig. 2). In this paper, we describe the synthesis and structure-activity rela- Drug Discovery Research, Astellas Pharma Inc.; 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Received November 30, 2009; accepted January 26, 2010; published online January 27, 2010 In the search for potent and selective human b b3-adrenergic receptor (AR) agonists as potential pharmacotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human b b3-, b b2-, and b b1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methylthiazol-...

Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric Henry Reaction

“…Although the early example of the mirabegron synthesis described the final acylation step of ( R )- 26 with the N -Boc protected secondary aliphatic amine, it has been revealed later that the reactivity of the primary aromatic amino and secondary aliphatic amino groups of ( R )- 26 can be distinguished fundamentally under specific reaction conditions. The Steglich-type acylation of ( R )- 26 with 2-amino-4-thiazoleacetic acid using the EDCl reagent in acidic aqueous environment acylates selectively the incompletely protonated and hence more nucleophilic primary aromatic nitrogen of ( R )- 26 .…”

Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects

“…A number of papers ,, and patents have described potent β 3 -AR agonists with either arylethanolamine or aryloxypropanolamine scaffolds. To discover a novel class of potent and selective β 3 -AR agonists, we synthesized a series of phenylethanolamine analogues having a bicyclic heteroaromatic ring such as indazole, isoquinoline, 1 H -pyrazolo­[3,4- b ]­pyridine, benzoisoxazole, benzoisothiazole, or benzoimidazole (Figure ).…”

Engineering of Cascade Reactions and Alditol Oxidase for High‐Yielding Synthesis of (R)‐Phenylethanolamine from Styrene, l‐Phenylalanine, Glycerol or Glucose

“…( R )‐phenylethanolamine (PEA) is a useful and important chiral intermediate in organic synthesis, pharmaceutical manufactory and medicinal chemistry. While its structure widely presents in numerous natural products such as bioactive alkaloids, [1] some derivatives have been developed as beta‐3 adrenergic agonist drugs [2] for treating obesity and non‐insulin dependent diabetes (type II) such as Myrbetriq, [3] or as a Sonic hedgehog signaling inhibitor [4] . Due to its strong cardiovascular activity, PEA sulfate salt, Apophedrin, is used as topical vasoconstrictor [5] …”