Isomers of erythro-5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril, a new bronchodilator

Abstract

The isomers of erythro-5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril (1), a new potent and beta2-selective bronchodilator, were synthesized by optical resolution of compound 1 and inversion of the erythro to the threo isomers. The isomers were tested for activities to inhibit histamine-induced bronchospasm and to increase the heart rate of anesthetized dogs. Racemic and (-)-erythro-1 showed potent and beta2-selective bronchodilater activities. Among the isomers, (-)-erythro-1 showed the highest activities and (+)-erythro-1 showed the lowest.

Development of Therapeutics That Induce Mitochondrial Biogenesis for the Treatment of Acute and Chronic Degenerative Diseases

“…Interestingly, in models of cardiac dysfunction, beta-1 adrenergic receptor stimulation by dobutamine ( 59 ) increases cell death and inflammation, but its blockade by the beta-1 selective antagonist metoprolol ( 60 ) enhances PGC-1α activation and improves cardiac metabolism and function. , Our laboratory has studied beta-2 adrenergic receptor selective agonists in renal MB. In particular, formoterol ( 61 ), fenoterol ( 62 ), and procaterol ( 63 ) induced MB in vitro at pharmacologically relevant doses. , Compound 61 has been confirmed to induce MB in vivo in naïve mice as well as in mice subjected to AKI, and this was associated with improvements in renal function, indicating that formoterol has therapeutic promise for treating AKI. However, other beta-2 adrenergic receptor agonists such as clenbuterol ( 64 ) and isoetharine ( 65 )did not induce MB in vitro , suggesting that biased agonism can be exploited to develop more effective mitochondrial biogenic beta-2 adrenergic receptor agonists.…”

“…319–320 Our laboratory has studied beta-2 adrenergic receptor selective agonists in renal MB. In particular, formoterol ( 61 ), 321 fenoterol ( 62 ), 322 and procaterol ( 63 ) 323 induced MB in vitro at pharmacologically relevant doses. 324–325 Compound 61 has been confirmed to induce MB in vivo in naïve mice as well as in mice subjected to AKI, 326 and this was associated with improvements in renal function, indicating that formoterol has therapeutic promise for treating AKI.…”

Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor

“…In 1976, a series of β-agonists based upon 8-hydroxycarbostyril were synthesized which subsequently lead to the development of the selective β 2 -agonist procaterol (Yoshizaki et al 1976(Yoshizaki et al , 1977. Because some of these agonists showed high potency for stimulating βAR responses and good chemical stability, additional 8-hydroxycarbo-styril derivatives containing side chain phenyl substituents were synthesized by Milecki et al (1987).…”

“…More recently TA 2005, an 8-hydroxycarbostyril derivative related to carbo-amine, was shown by radioligand binding assays and in isolated tissue studies to also tightly bind to the βAR (Voss et al 1992). Although a number of studies have characterized potent and selective β-agonists, including several using the 8-hydroxycarbostyril (Yoshizaki et al 1976(Yoshizaki et al , 1977Hieble 1991;Ruffolo et al 1995), the chemical structures of 8-hydroxycarbostyril-based β-agonists that contribute to high affinity binding and/or slow dissociation have not been defined.…”

Preparation of diastereomeric β-d-glucuronides of the bronchodilator procaterol using immobilized rabbit liver microsomal enzymes

“…In addition, procaterol contains two chiral centres which give rise to the possibility of diastereomeric conjugates with optically active glucuronic acid. Procaterol is given as the racemate of the erythro form (3); therefore, in addition to regioselectivity, enantioselectivity may occur during gillclironidation. This report describes the biosynthesis of procaterol gilicuronides by an immobilized liver microsomal enzyme system (4)(5)(6) and the characterization of the regio-and enantioselectivity of procaterol gillclironidation.…”