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  • In summary the different types of interstitial cells found i

    2024-06-14

    In summary, the different types of interstitial cells found in the current study are illustrated in Fig. 7A (see legend for further details), which is suggestive of a heterogeneous complex network of interstitial cells communicating with each other. The possible signaling pathways involving this interstitial cell network are illustrated in Fig. 7B. It would appear that the interstitial cell network releases and responds to catecholamines. It can be hypothesized that this kind of chemical signaling might influence the surrounding interstitial cell network and the detrusor affecting micro-contractile activity.
    Conclusions
    The human gene which encodes the β-adrenergic receptor (β-AR) was discovered in the 1980s and opened a field of exploration around its function in metabolic processes. Highly expressed in adipose tissue, it is involved in regulating lipolysis and thermogenesis., Due to its role in these processes, β-adrenergic receptor agonists were investigated as a potential treatments for obesity and diabetes. As a result of this research, several compounds entered clinical trials but failed to demonstrate the sustained weight loss efficacy exhibited in rodents which resulted in diminished interest in the pursuit of these pharmacological indications. Subsequent research exposed evidence of β-AR expression in the Finasteride detrusor muscle in multiple species including humans. Furthermore, β-AR agonists were demonstrated to relax bladder detrusor muscle strips as well as increase bladder capacity in rodent cystometry studies., , In light of these discoveries, β-AR agonists became desirable targets throughout the pharmaceutical industry for the treatment of overactive bladder (OAB)., OAB is a highly prevalent disorder, particularly among the elderly population, with symptoms of urinary urgency, with or without urgency incontinence, and often with frequency and nocturia. It is an underdiagnosed condition that negatively affects the quality of life of millions of people. Pharmacological agents for treating OAB have evolved over the past two decades resulting in clinically approved drugs such as mirabegron (YM-178, , ). Our group’s research efforts over the past several years has primarily focused on constraining the linear ethanolamine moiety present in many of the first generation β-AR agonists such as , resulting in a novel pyrrolidine scaffold. Extensive SAR (structure-activity relationship) evaluations in this series led to the discovery of many potent and selective human β-AR agonists with improved metabolic stabilities. Our key discovery, vibegron (, ), is emblematic of this research and has recently progressed into Phase 3 clinical trials. Compounds and as well as other lead compounds in that series are all aniline-derived amides. In search for continued structural diversity, our group focused on a series of RHS (right-hand side) benzamide (reverse amides) while keeping the pyrrolidine core intact. Initial efforts leveraging parallel synthesis resulted in promising leads in potent and selective analogs such as piperidine ethyl ester () with modest potency (human β-AR EC=63nM). Subsequent optimization further improved the overall profile of these compounds to afford the highly potent and selective 3.1.0 azabicyclic ethyl oxadiazole () (β EC=3.1nM, β and β IC>20μM). Compound was thoroughly profiled and exhibited improvements within the series in PK across species (). Despite these advances, however, the overall profile exhibited a low probability of achieving our target of QD dosing in humans. In our search for more optimal PK profiles in the benzamide series, a unique class of piperazine derivatives was discovered and will be the focus of this report. Our group previously published synthetic approaches towards the pyrrolidine aniline core which allowed efficient parallel synthesis of compounds leading up to, and including, vibegron., This work provided the foundation for modifications resulting in the synthesis of the benzoic acid core which in turn was utilized to evaluate the SAR of benzamides such as and . In an effort to further streamline the synthetic sequence, the group developed a more convergent, high yielding and diastereoselective route whereby either the aniline or benzoic acid could be installed from a common acetylene intermediate as presented in . The first step in the synthesis involved installation of chiral auxiliary, ()-4-phenyl-2-oxazolidinone, via acid chloride coupling with hexynoic acid resulting in the -acyloxazolidinone . A subsequent magnesium chloride catalyzed anti-Aldol reaction with benzaldehyde converted into intermediate with excellent diastereoselectivity. The chiral oxazolidinone auxiliary was then removed via hydrolysis in aqueous LiOH/HO to furnish acid intermediate . The alcohol of was then protected as a TBS ether in the presence of DBU and a subsequent Curtius rearrangement with 4-methoxybenzyl alcohol yielded the key 4-methoxybenzyloxycarbonyl (Moz) protected amino acetylene intermediate . Coupling of 4-iodomethylbenzoate with the terminal alkyne under Sonogashira conditions afforded the methyl ester acetylene . Deprotection of the Moz group with TFA set up amine for a palladium catalyzed cyclization to a 2,3-dihydropyrrole intermediate which was subsequently reduced via platinum catalyzed hydrogenation resulting in the highly diastereoselective formation of pyrollidine isomer . The pyrrolidine was then sequentially Boc protected () and then TBS deprotected with TBAF to furnish intermediate . Finally, the desired benzoic acid handle was formed upon hydrolysis of the methyl ester under standard aqueous lithium hydroxide conditions to afford the desired coupling key intermediate .