Discovery of a Novel Series of Biphenyl Benzoic Acid Derivatives as Highly Potent and Selective Human β3 Adrenergic Receptor Agonists with Good Oral Bioavailability. Part II

Abstract

The left-hand side (LHS) and central part of our first generation biphenyl (FGB) series was modified to improve in vitro and in vivo beta3-AR potency without loss of oral bioavailability. First, in this study, we focused our efforts on replacement of the 3-chlorophenyl moiety in the LHS of FGB analogues with 3-pyridyl ring analogues to adjust the lipophilicity. Second, we investigated the replacement of the central part of this series and discovered that introduction of a methyl group into the alpha-position of the phenethylamine moiety greatly enhanced potency keeping good oral availability. Finally, the replacement of the two carbon linker of the central part with an ethoxy-based linker provided improved potency and PK profiles. As a result of these studies, several analogues (i.e., 9h, 9k, 9l, 10g, 10m, 10p, 10r, 11b, and 11l) were identified that displayed an excellent balance of very higher human beta3-AR potency compared to the FGB compounds, high selectivity, and good pharmacokinetic profiles. Furthermore, these several compounds showed high in vivo efficacy in an overactive bladder (OAB) model. These findings suggest that our selected second generation biphenyl (SGB) series compounds may be attractive new successful therapeutic candidates for the treatment of OAB.

Discovery of Highly Potent and Selective Biphenylacylsulfonamide-Based β3-Adrenergic Receptor Agonists and Evaluation of Physical Properties as Potential Overactive Bladder Therapies: Part 5

“…To address this problem, a series of second generation biphenyl (SGB) analogues were developed, with adjustment of physical properties by replacement of the phenyl moiety with pyridine analogues on the left-hand side (LHS), resulting in enhanced potency and maintenance of good oral availability as shown in Table 1. 11 In a previous metabolism study of FGB/SGB analogues conducted in rat and human hepatocytes, we identified two main metabolites: a dealkylated metabolite (M-1) and an acylglucuronide conjugated metabolite (M-2) as shown in Scheme 1. 12 Although glucuronide metabolites from phase II metabolism generally enhance elimination in bile and urine, they can also transform into their covalent adducts which can lead to toxicity.…”

“…In our previous study, we described a series of first generation biphenyl (FGB) analogues, shown in Figure , which exhibited good oral bioavailability and a long plasma half-life . The key to success was finding a benzoic acid moiety and R substitution on the right-hand side (RHS) which maximized β 3 -AR activity, selectivity, and bioavailability.…”

“…On the other hand, SAR studies of the R position on the terminal phenyl ring in the FGB analogues indicated that introduction of lipophilic substitute group led to increased potency for β 3 -AR activity (O-cyclohexyls 1e , 2e > O-isopropyls 1b , 2b > O-methyl 1a ), but a decreased oral bioavailability ( 1a > 1b , 2b > 1e , 2e ) while displaying high passive permeability and good stability to liver microsomes. To address this problem, a series of second generation biphenyl (SGB) analogues were developed, with adjustment of physical properties by replacement of the phenyl moiety with pyridine analogues on the left-hand side (LHS), resulting in enhanced potency and maintenance of good oral availability as shown in Table . In a previous metabolism study of FGB/SGB analogues conducted in rat and human hepatocytes, we identified two main metabolites: a dealkylated metabolite (M-1) and an acylglucuronide conjugated metabolite (M-2) as shown in Scheme .…”

“… a See refs and . b Dose 0.10 or 0.20 mg/kg po ( n = 2, 3). c The ratio is defined as the C max of each compound divided by the C max of 1b . The ratio value of 1b was presented as 1.0. …”

Synthesis of the β3-Adrenergic Receptor Agonist Solabegron and Analogous N-(2-Ethylamino)-β-amino Alcohols from O-Acylated Cyanohydrins – Expanding the Scope of Minor Enantiomer Recycling

“…In the catalytic hydrogenation to obtain amino alcohol ( R )- 15 , using conditions identical to those used for the other substrates, only a slight decrease in enantiomeric excess was observed (97% to 94%). In order to reduce the amide to an amine without reducing the ester functionality, we used a modified literature procedure employing borane dimethylsulfide complex; this transformation gave the known compound ( R )- 16 with an enantiomeric excess of 95%. Final hydrolysis of the ester function to the carboxylic acid was accomplished following a literature procedure using LiOH .…”