Discovery of a Novel and Potent Human and Rat .BETA.3-Adrenergic Receptor Agonist, [3-[(2R)-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic Acid

Abstract

1) This sub-classification has led to the development of b 1 -and b 2 -AR antagonists and/or agonists which have been useful for the treatment of cardiovascular diseases and asthma. In early 1980s, a third b-AR, initially referred to as "atypical"2) and later called b 3 -AR has been found in a number of species, including man, [3][4][5][6] and in 1989, the human, 7) rat, 8) and mouse 9) b 3 -ARs were first cloned and characterized. Like other b-ARs, b 3 -ARs belong to the G-protein-coupled receptor family that includes receptors with a common structure consisting of seven transmembrance-spanning connected by interhelical loops.10) The b 3 -AR is located on the surface of both white and brown adipocytes and is known to be stimulated by endogenous catecholamines, adrenalin, and noradrenaline. It has also been reported that b 3 -AR receptor plays a significant role in regulating lipolysis and thermogenesis in rodent and human adipose tissues. 11,12) Moreover, studies of b 3 -AR mRNA demonstrated that, b 3 -ARs exist in human heart, gall bladder, gastrointestinal tract, prostate, and urinary bladder detrusor tissue in addition to adipocytes. [13][14][15][16] Since the discovery of b 3 -AR, a number of laboratories have been engaged in developing potent and selective b 3 -AR agonists for the treatment of various metabolic and gastrointestinal diseases such as obesity, non-insulin dependent (Type-II) diabetes, irritable bowel syndrome, and urinary frequency and incontinence. [17][18][19][20][21] Early b 3 -AR agonists (the "first generation" of potent and selective rat b 3 -AR agonists) such as BRL 37344 (BRL 35135), [22][23][24] CL 316243, [25][26][27] and SR 58611A, 28) having a 3-chlorophenyl moiety in the left-hand side (LHS) and a carboxylic acid or an ester functionality in the right-hand side (RHS) as shown in Chart 1, have been reported to be effective anti-obesity and anti-diabetic agents in rodents.29) These compounds, through their potent agonistic activity for the b 3 -AR, stimulate lipolysis and energy expenditure and cause only a slight increase in heart rate (b 1 -AR activity) and weak muscle tremor (b 2 -AR activity). Unfortunately, some of these early b 3 -AR agonists developed for the treatment of metabolic disorders failed to produce similar effects in humans, due to a lack of selectivity and/or potency, or poor pharmacokinetics.30) Because of structural differences between human and rat b 3 -ARs with regard to the amino acid sequences of each receptor, activity at the rat b 3 -AR could not effectively predict that at the human b 3 -AR.31) Thus, a new generation of human b 3 -AR agonists with minimal side effects associated with activation of human b 1 -and b 2 -ARs has long been needed.A new generation of b 3 -AR agonists currently under preclinical development is represented by the tetrahydroisoquinoline 1, [32][33][34] SB 226552, 35,36) L 755507, 37) L 770644, 38,39) and LY-377604 40) (Chart 1). These compounds having both potent and full agonistic activity, and high selectivity at the human b...

Effects of a novel β3‐adrenoceptor agonist, AJ‐9677, on relaxation of the detrusor muscle: An in vitro study

“…Recently, several β 3 ‐AR agonists were synthesized, and their effects on energy homeostasis were examined in animals in terms of anti‐obesity and anti‐diabetes. AJ‐9677, [3‐[(2R)‐[[(2R)‐(3‐chlorophenyl)‐2‐hydroxyethyl]amino]propyl]‐1H‐indol‐7‐yloxy]‐acetic acid, being a novel selective β 3 ‐AR agonist, was developed as anti‐obesity and anti‐diabetic agents 15–18 . Furthermore, AJ‐9677 exerts a 100‐ to 200‐fold higher affinity to β 3 ‐AR than to β 2 ‐AR and β 1 ‐AR, respectively 16 .…”

“…AJ‐9677, [3‐[(2R)‐[[(2R)‐(3‐chlorophenyl)‐2‐hydroxyethyl]amino]propyl]‐1H‐indol‐7‐yloxy]‐acetic acid, being a novel selective β 3 ‐AR agonist, was developed as anti‐obesity and anti‐diabetic agents 15–18 . Furthermore, AJ‐9677 exerts a 100‐ to 200‐fold higher affinity to β 3 ‐AR than to β 2 ‐AR and β 1 ‐AR, respectively 16 . Despite of a high potency of this compound for the treatment of OAB, the relaxant effects on the detrusor muscle has not been yet clarified.…”

Subject Index to Volume 12

“…Extensive SAR study on substituents of the indole ring produced a potent and selective β 3 -agonist, AJ-9677 (24) [43,44]. Extensive SAR study on substituents of the indole ring produced a potent and selective β 3 -agonist, AJ-9677 (24) [43,44].…”

Synthesis of New 1H‐Indazoles through Diels–Alder Transformations of 4‐Styrylpyrazoles under Microwave Irradiation Conditions

“…[1][2][3][4][5][6] Many synthetic indazoles, however, are known and recognized by their pharmaceutical activity, which has inspired the development of a number of new syntheses for the indazole ring system. [7][8][9][10] Certain indazoles act as dopamine D2 receptor antagonists, [11][12][13] antipyretic and anti-inflammatory agents (bendazac and benzidamine), [14] analgesics [15,16] or anti-HIV protease [17,18] and Rho kinase inhibitors [19,20] and are used in the treatment of diabetes [7,21,22] and obesity. [23] Other derivatives exhibit antitumour (combretastatin), [24][25][26][27][28] CNS (granisetron), [8] bronchodilatory, vasodilatory or neuroprotectant activities.…”