Synthesis and Evaluation of Potent and Selective β₃ Adrenergic Receptor Agonists Containing Acylsulfonamide, Sulfonylsulfonamide, and Sulfonylurea Carboxylic Acid Isosteres

Abstract

Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3), beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.

Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug Discovery

“…Since the sulfonamide, acylsulfonamide, and sulfonylurea groups contain electronwithdrawing groups in proximity to a nitrogen atom, these isosteres are comparable to carboxylates in terms of acidity but have no potential to form acyl glucuronides. Additionally, these acid surrogates may offer a new tether for the synthetic modulation of pharmacological and/or pharmacokinetic properties (102,103).…”

Enantioselective synthesis of (S)-phenylephrine by whole cells of recombinant Escherichia coli expressing the amino alcohol dehydrogenase gene from Rhodococcus erythropolis BCRC 10909

“…Corynebacterium sp. ST-10 with NAD + -dependent phenylacetaldehyde reductase activity can be used in the conversion of 2-chloro-1-(3-chlorophenyl)ethanone to 2-chloro-1-(3-chlorophenyl)ethanol, a precursor for the synthesis of ␤ 3 adrenergic receptor agonists [21,22]. Very recently, Escherichia coli cells that express the l-1- amino-2-propanol dehydrogenase (AADH) gene from Rhodococcus erythropolis MAK154 have been demonstrated to possess the capacity to reduce (S)-1-phenyl-2-methylamino-propan-1-one (MAK) to d-PDE [23].…”

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β3‐Adrenoceptor Agonists

“…Therefore, we designed a few sets of new molecules taking into account our knowledge and the molecular features of many described b 3 -AR ligands, the right-hand-side moieties of which (RHS, Figure 2) usually bear substituents capable of forming hydrogen bonds, such as phenols, anilines, acetamides, benzamides, and methylsulfonamides. [16,17] Compounds containing aliphatic and arylsulfonamide moieties were also synthesized, and the alkylsulfonamides were found to be less potent than the corresponding aromatic analogues. Thus, the benzenesulfonamide moiety represents a group of choice to prepare potent and selective agonists of the human b 3 -adrenoceptor.…”