Single Chemical Entity Research Articles

A New Avenue for Enhanced Treatment of Hyperuricemia and Oxidative Stress: Design, Synthesis and Biological Evaluation of Some Novel Mutual Prodrugs Involving Febuxostat Conjugated with Different Antioxidants

Febuxostat (FEB) is the first non-purine xanthine oxidase inhibitor (XOI) used for the treatment of hyperuricemia and gout. The oxidative stress induced by reactive oxygen species (ROS) which accompany purine metabolism by XO, could contribute to cellular damage and several pathological conditions. In this view, the present work addresses the evaluation of combining the hypouricemic effect of FEB and the free radical scavenging potential of various natural antioxidants in a single chemical entity by implementing the “mutual prodrug” strategy. Accordingly, a series of five ester prodrugs containing FEB together with different naturally occurring antioxidants namely, thioctic acid (4), thymol (5), menthol (6), vanillin (7), and guaiacol (8) was synthesized. Prominently, all the chemically conjugated prodrugs (4 – 8) revealed an obvious increase in the hypouricemic and antioxidant potentials when compared with their corresponding promoieties and physical mixtures. Moreover, they showed a potential protective effect against CCl4-induced hepatotoxicity and oxidative stress, together with no cytotoxicity on normal breast cells (MCF10A). Furthermore, the in vitro chemical and enzymatic stability studies of the prodrugs (4 – 8) using a developed HPLC method, verified their stability in different pHs, and rapid hydrolysis in rabbit plasma and liver homogenate to their parent metabolites. Moreover, the prodrugs (4 – 8) showed higher lipophilicity and lower aqueous solubility when compared to the parent drugs. Finally, the obtained merits from the implementation of the mutual prodrug strategy would encourage further application in the development of promising candidates with high therapeutic efficacy and improved safety profiles.

Serum albumin binding knob domains engineered within a VH framework III bispecific antibody format and as chimeric peptides.

Serum albumin binding is an established mechanism to extend the serum half-life of antibody fragments and peptides. The cysteine rich knob domains, isolated from bovine antibody ultralong CDRH3, are the smallest single chain antibody fragments described to date and versatile tools for protein engineering. Here, we used phage display of bovine immune material to derive knob domains against human and rodent serum albumins. These were used to engineer bispecific Fab fragments, by using the framework III loop as a site for knob domain insertion. By this route, neutralisation of the canonical antigen (TNFα) was retained but extended pharmacokinetics in-vivo were achieved through albumin binding. Structural characterisation revealed correct folding of the knob domain and identified broadly common but non-cross-reactive epitopes. Additionally, we show that these albumin binding knob domains can be chemically synthesised to achieve dual IL-17A neutralisation and albumin binding in a single chemical entity. This study enables antibody and chemical engineering from bovine immune material, via an accessible discovery platform.

Structure-based drug design of multi-targeting inhibitors of human pathogen fungi

The development of multi-targeting inhibitors is proposed to improve the antifungal effect. In a single chemical entity it is possible to inhibit two different targets. Thioredoxin reductase and glutathione reductase belong to the two main systems responsible for the maintenance of cell homeostasis. Herein, we describe the discovery and selection of dual-inhibitors targeting thioredoxin reductase and glutathione reductase proteins of Aspergillus fumigatus. Both proteins were modeled and molecular dynamics were performed to obtain different conformational frames to ensemble docking. After the independent virtual screening of each protein, a ranking containing molecules selected for both proteins were generated. Fourteen molecules were tested in vitro against A. fumigatus, Fusarium oxysporum, Paracoccidioides brasiliensis, Candida albicans and Cryptococcus neoformans by broth microdilution assay. Octenidine (OCT) was the most promising molecule which exhibited MIC < 0.5 µg/mL for all fungi tested. The literature describes the action of OCT in the cell membrane of gram-negative bacteria. Thus, we assume that the mechanism in which OCT acts on fungal cells is an association of disrupting the cell membrane and also the dual-inhibition of thioredoxin reductase and glutathione reductase which implies the increase of ROS and further fungal cell death.

Synthesis and anti-Alzheimer potential of novel α-amino phosphonate derivatives and probing their molecular interaction mechanism with acetylcholinesterase

Pleiotropic interference may be a prerequisite for the efficient limitation of the progression of multi-factorial diseases such as Alzheimer's disease (AD). Concept of designing the single chemical entity acting on two or more targets of interest has potential advantage in AD therapy. In line with this, rational design and synthesis of frame work of hybrids bearing 2,3-disubstituted quinazolinone, vanillin and α-amino phosphonate scaffolds (5a─v) were carried out. A congeneric set of twenty-two synthetic derivatives (5a─v) were evaluated for their cholinesterase inhibitory, antioxidant, DNA nicking, DNA protection, neuroprotective and Aβ aggregation modulatory activities. Amongst tested activities, the most significant and worth mentioning is that the analogues 5m, 5p and 5u were found to be the most potent, selective, and mixed type inhibitors of EeAChE with IC50 values of 0.296 ± 0.030, 0.289 ± 0.027, and 0.306 ± 0.028 μM, respectively. Further, the biophysical approaches indicated that the compounds 5m, 5p, and 5u have a strong binding affinity towards AChE. Kinetic and Molecular docking studies have revealed that the most active congeners were well oriented in the AChE active site by interacting with both catalytic active site (CAS) and peripheral anionic site (PAS). A few parameters derived from molecular dynamics (MD) simulation trajectories emphasized the stability of AChE-5p and 5m complexes throughout the 100 ns simulations, and the local conformational changes of the residues of AChE validate the stability of AChE-5p and 5m complexes. Further, these derivatives significantly impacted ABTS radical scavenging capacities and maximal DNA protection activity. Importantly, Thioflavin T (ThT) assay and FE-SEM study demonstrated compounds 5m, 5p and 5u as effective Aβ1−42 fibril modulators at molecular level by the formation of micro size co-assembled mature structures, thus efficiently abolishing the cytotoxicity of Aβ1–42. Finally, these active compounds are determined to be non-toxic and highly neuroprotective against H2O2-induced cell death in SK-N-SH cell lines. Furthermore, in silico ADMET prediction studies have revealed that the targeted analogues satisfied most of the characteristics of CNS acting drugs. These multi-functional efficacies indicated worthiness of these α-amino phosphonate derivatives being chosen for further pharmacokinetics, toxicity, and behavioral research to test their potential for AD treatment.

The Antidepressant-like Activity, Effects on Recognition Memory Deficits, Bioavailability, and Safety after Chronic Administration of New Dual-Acting Small Compounds Targeting Neuropsychiatric Symptoms in Dementia.

This study aimed to extend the body of preclinical research on prototype dual-acting compounds combining the pharmacophores relevant for inhibiting cyclic nucleotide phosphodiesterase 10 (PDE10A) and serotonin 5-HT1A/5-HT7 receptor (5-HT1AR/5-HT7R) activity into a single chemical entity (compounds PQA-AZ4 and PQA-AZ6). After i.v. administration of PQA-AZ4 and PQA-AZ6 to rats, the brain to plasma ratio was 0.9 and 8.60, respectively. After i.g. administration, the brain to plasma ratio was 5.7 and 5.3, respectively. An antidepressant-like effect was observed for PQA-AZ6 in the forced swim test, after chronic 21-day treatment via i.p. administration with 1 mg/kg/day. Both compounds revealed an increased level of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus and prefrontal cortex. Moreover, PQA-AZ4 and PQA-AZ6 completely reversed (+)-MK801-induced memory disturbances comparable with the potent PDE10 inhibitor, compound PQ-10. In the safety profile that included measurements of plasma glucose, triglyceride, and total cholesterol concentration, liver enzyme activity, the total antioxidant activity of serum, together with weight gain, compounds exhibited no significant activity. However, the studied compounds had different effects on human normal fibroblast cells as revealed in in vitro assay. The pharmacokinetic and biochemical results support the notion that these novel dual-acting compounds might offer a promising therapeutic tool in CNS-related disorders.

Recent pharmaceutical engineered trends as theranostics for Japanese encephalitis

Japanese encephalitis virus (JEV) is a zoonotic virus transmitted due to the bite of Culex mosquito species and leads to severe viral encephalopathy. JEV’s basic structure is comprised of a positive single-stranded virus that causes a corona of clinical and neurological manifestations. Different live and killed prophylactic vaccines are available as prophylaxis against JEV. Yet, no single chemical entity as an antiviral agent is available to counteract the JEV menace. Despite the breakthrough development in vaccines, JEV is a paramount virus in suburban and rural areas of South Asia and the western pacific with a prospective to become a dominant vector worldwide. So, the population residing in this area is affected by irregular health services that devoid them from vaccination drive against JEV virus. This review outline’s structural and neuro-penetration events of JEV, current treatment modalities with challenges associated with it and latest treatment sophistications, and the application of advanced pharmaceutical techniques in diagnosis, treatment and recent trends in diagnostics like ELISA, RT-PCR, Immunofluorescence based and molecular based assays, therapeutic (both synthetic and natural origin antivirals) and clinical interventions with vaccines and immunomodulatory agents are discussed in this review.

Mapping Markush

Markush structures are molecular skeletons containing not only specific atoms but al-so placeholders to represent broad sets of chemical (sub)structures. They allow a vast number of compounds (e.g., 10^16 different compounds within patent EP 0810 209) to be claimed in a patent application without having to specify every single chemical entity. While Markush structures raise important questions regarding the functioning of the patent system, innova-tion researchers have been surprisingly silent on the topic. This paper summarizes the ongo-ing policy debate about Markush structures and provides first empirical insights into how Markush structures are used in patent documents in the pharmaceutical industry and how they affect important outcomes in the patent prosecution process. While not causing frictions in the patent prosecution process, patent documents containing Markush structures have an increased likelihood to restrict the patentability of follow-on inventions and to hamper the entry of generic competition in the product market.

Comparative Assessment of Polyherbal Formulation and Mucuna pruriens Extract as Neuroprotectant by Using MPTP Screening Mouse Model of Parkinson’s Disease

Background: The main aim of the study was to compare the neuroprotective potential of Polyherbal Formulation (PHF) with that of an extract of a well-reported anti-parkinson plant, i.e., Mucuna pruriens. Methods: Different PHF combinations (PHFs) were formulated by using hydro-alcoholic extracts and were tested for neuroprotective potential against Mucuna pruriens extract (MPE). In the experimental study, 30 albino mice (Swiss strain, 35-45g) were grouped into Control, MPTP, MPTP+ MPE, MPTP+PHFs, MPTP+ L-DOPA groups. Experimental mice were given PHFs and MPE (50 mg/kg body wt.) by intraperitoneal routes. MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) was given orally for 2 weeks with prior use of PHFs and MPE 20 mg/kg body wt. for 2 weeks. After treatment, a neurobehavioral study was performed as well as neurochemical parameters were evaluated. Results: The results showed that polyherbal formulation improved the performance of the dopaminergic neurons in the substantia nigra region of the brain compared to MPE with respect to MPTP intoxication. A significant reduction was found in spontaneous locomotor activity and rotarod activity in MPTP treated mice in contrast with the control group, in whom these activities were restored by MPTP+MPE and MPTP+PHF1; however, this contrasted with the standard L-Dopa treatment group. This improvement was observed to be significantly better in the MPTP+PHF1 treated group compared to the treatment group of MPTP+MPE. The changes in different parameters occurred after the MPTP treatment. These changes were observed in the levels of malondialdehyde (MDA), conjugated dienes (CD), superoxide dismutase (SOD), and catalase. Conclusion: The study concluded that PHF treatment promotes significant neurogenesis, reduces apoptosis, promotes antioxidant capacity, and restores dopamine levels. PHF contains numerous classes of chemical constituents, which show a synergistic effect for better therapeutic remuneration and neuroprotection compared to the single chemical entity L-DOPA, which is a well-known chemical constituent present in MPE.

Mapping Markush

Markush structures are molecular skeletons containing not only specific atoms but also placeholders to represent broad sets of chemical (sub)structures. As genus claims, they allow a vast number of compounds to be claimed in a patent application without having to specify every single chemical entity. While Markush structures raise important questions regarding the functioning of the patent system, innovation researchers have been surprisingly silent on the topic. This paper summarizes the ongoing policy debate about Markush structures and provides first empirical insights into how Markush structures are used in patent documents in the pharmaceutical industry and how they affect important outcomes in the patent prosecution process. While not causing frictions in the patent prosecution process, patent documents containing Markush structures have an increased likelihood to restrict the patentability of follow-on inventions and to facilitate the construction of broad patent fences.

Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands.

The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first CB2R heterobivalent bitopic ligands. In contrast to the parent orthosteric compound, our bitopic ligands selectively target CB2R versus CB1R and show a functional selectivity for the cAMP signaling pathway versus βarrestin2 recruitment. Moreover, the most promising bitopic ligand FD-22a displayed anti-inflammatory activity in a human microglial cell inflammatory model and antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Finally, computational studies clarified the binding mode of these compounds inside the CB2R, further confirming their bitopic nature.

Design, synthesis and bioevaluation of new vanillin hybrid as multitarget inhibitor of α-glucosidase, α-amylase, PTP-1B and DPP4 for the treatment of type-II diabetes.

Diabetes mellitus (DM) is a real challenge to the recent era and is one of the major diseases for initiating life-threatening disorders. In current research, a compound was designed by combining vanillin, thiazolidinedione and morpholine. The goal of our designed work is to demonstrate the ability of our design compound (9) to modulate more than one target responsible for hyperglycemia at the same time. The synthesized compound was able to show good to moderate inhibition potential against α-glucosidase, α-amylase and protein tyrosine phosphatase 1B. However, it exhibited excellent in-vitro inhibition of Dipeptidyl peptidase-4 (DPP-4) with IC50 value of 0.09µM. Antioxidant activity by using DPPH assay also showed its good antioxidant potential. In in-vivo experiments, the compound 9 was proved to be safe in experimental mice. The activity profile of the compound was observed for 21 days which showed that the compound was also effective in experimental mice. Binding orientations and Interactions with key amino acid residues of the selected targets were also studied by using docking studies. Overall, we were successful in synthesizing multitarget preclinical therapeutic by combining three pharmacophoric moieties into a single chemical entity that can modulate more than one target at the same time.

Neuroendocrine tumor theranostics.

Theranostics is a term coined by combining the words “therapeutics” and “diagnostics,” referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body, and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma‐emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta‐emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, 111Lu‐DOTATATE (Lutathera), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly address the Japanese point of view regarding the development of new radiopharmaceuticals.

Developing a Rational, Optimized Product of Centella asiatica for Examination in Clinical Trials: Real World Challenges.

Botanical products are frequently sold as dietary supplements and their use by the public is increasing in popularity. However, scientific evaluation of their medicinal benefits presents unique challenges due to their chemical complexity, inherent variability, and the involvement of multiple active components and biological targets. Translation away from preclinical models, and developing an optimized, reproducible botanical product for use in clinical trials, presents particular challenges for phytotherapeutic agents compared to single chemical entities. Common deficiencies noted in clinical trials of botanical products include limited characterization of the product tested, inadequate placebo control, and lack of rationale for the type of product tested, dose used, outcome measures or even the study population. Our group has focused on the botanical Centella asiatica due to its reputation for enhancing cognition in Eastern traditional medicine systems. Our preclinical studies on a Centella asiatica water extract (CAW) and its bioactive components strongly support its potential as a phytotherapeutic agent for cognitive decline in aging and Alzheimer's disease through influences on antioxidant response, mitochondrial activity, and synaptic density. Here we describe our robust, scientific approach toward developing a rational phytotherapeutic product based on Centella asiatica for human investigation, addressing multiple factors to optimize its valid clinical evaluation. Specific aspects covered include approaches to identifying an optimal dose range for clinical assessment, design and composition of a dosage form and matching placebo, sourcing appropriate botanical raw material for product manufacture (including the evaluation of active compounds and contaminants), and up-scaling of laboratory extraction methods to available current Good Manufacturing Practice (cGMP) certified industrial facilities. We also address the process of obtaining regulatory approvals to proceed with clinical trials. Our study highlights the complexity of translational research on botanicals and the importance of identifying active compounds and developing sound analytical and bioanalytical methods for their determination in botanical materials and biological samples. Recent Phase I pharmacokinetic studies of our Centella asiatica product in humans (NCT03929250, NCT03937908) have highlighted additional challenges associated with designing botanical bioavailability studies, including specific dietary considerations that need to be considered.

Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge.

A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets ('polypharmacology'). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.

2-Hydroxy-5-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate: Synthesis, In Silico Analysis and In Vitro Pharmacological Evaluation

Quercetin and ferulic acid are two phytochemicals extensively represented in the plant kingdom and daily consumed in considerable amounts through diets. Due to a common phenolic structure, these two molecules share several pharmacological properties, e.g., antioxidant and free radical scavenging, anti-cancer, anti-inflammatory, anti-arrhythmic, and vasorelaxant. The aim of the present work was the combination of the two molecules in a single chemical entity, conceivably endowed with more efficacious vasorelaxant activity. Preliminary in silico studies herein described suggested that the new hybrid compound bound spontaneously and with high affinity on the KCa1.1 channel. Thus, the synthesis of the 3′-ferulic ester derivative of quercetin was achieved and its structure confirmed by 1H- and 13C-NMR spectra, HSQC and HMBC experiments, mass spectrometry, and elementary analysis. The effect of the new hybrid compound on vascular KCa1.1 and CaV1.2 channels revealed a partial loss of the stimulatory activity that characterizes the parent compound quercetin. Therefore, further studies are necessary to identify a better strategy to improve the vascular properties of this flavonoid.

Chiral Polythiophenes: Part I: Syntheses of Monomeric Precursors

The purpose of this mini-review is to comprehensively present the synthetic approaches used for the preparation of non-racemic mono- and multi-substituted thiophenes, which, in turn, can be applied as precursors for the synthesis of chiral polythiophenes isolated as a single chemical entity or having supramolecular thin-layer architectures.

Khat-drug interactions: A systematic review

Context: Consumption of khat leaves has been disseminated worldwide with the migration of its users from Arabia and Africa. Despite numerous reports regarding the associations of khat chewing with serious health impacts, a significant number of people worldwide uses khat daily, especially in its origin countries. The risk of co-administration of khat and drugs (prescription and over the-counter medications) is high among these individuals, leading to increase probability of adverse khat-drug interactions. The likelihood of khat-drug interactions could be higher than drug-drug interactions because drugs usually contain single chemical entities while almost all herbs (including khat) contain mixtures of pharmacologically active constituents. Aims: To review the literatures on how khat interacts with some drugs and whether it is favorable or not. Methods: The study was conducted as a systematic review. The electronic literature searches were made in Google search engine to access publications from databases like PubMed, Google Scholar, and Cochrane using the keywords ‘khat’, ‘Catha edulis’ in combination with the terms ‘drug interaction’, ‘adverse-effects’, ‘side effects’, ‘adverse drug reaction’, ‘safety’, and ‘toxicity’ to identify relevant articles. Results: A total of 250 articles was identified, and these articles were checked in terms of title, abstract, and content according to inclusion and exclusion criteria. Finally, 18 articles were included in the study. The khat use significantly interact with most drugs and may cause unpredictable pharmacological sequences. Conclusions: Healthcare providers suggest patients` khat abstinence during medication process. Future studies need to investigate the khat- clinical drugs interactions especially with chronic used drugs.

Pharmacotherapeutics In Prosthodontics – An Overview

Pharmacology is the science of drugs. Drug is the single active chemical entity present in a medicine that is used for diagnosis, prevention, treatment of a disease. Pharmacology deals with interaction of exogenously administered chemical molecules (drugs) with living systems. The two main aspects of concern are the effects of drugs on biological systems and the effect of biological systems on efficacy and metabolism of drugs. Drugs play an important role in improving the response of the patient in both pre-treatment and post-treatment phases. Drugs in dentistry act as a primary treatment modality as well as facilitator of dental procedures. With phenomenal growth of information on the mechanism of action and clinical application of drugs as well as rapid introduction of new drugs, pharmacology has become increasingly important to all dentists. Prosthodontics is that specialty of dentistry which deals with patients of all ages, hence making it more important to know about the local and systemic effects of drugs and their side effects.&#x0D; &#x0D;

Dual inhibition of CB1 receptors and iNOS, as a potential novel approach to the pharmacological management of acute and long COVID-19.

COVID‐19 (SARS‐CoV‐2) causes multiple inflammatory complications, resulting not only in severe lung inflammation but also harm to other organs. Although the current focus is on the management of acute COVID‐19, there is growing concern about long‐term effects of COVID‐19 (Long Covid), such as fibroproliferative changes in the lung, heart and kidney. Therefore, the identification of therapeutic targets not only for the management of acute COVID‐19 but also for preventing Long Covid are needed, and would mitigate against long‐lasting health burden and economic costs, in addition to saving lives. COVID‐19 induces pathological changes via multiple pathways, which could be targeted simultaneously for optimal effect. We discuss the potential pathologic function of increased activity of the endocannabinoid/CB1 receptor system and inducible NO synthase (iNOS). We advocate a polypharmacology approach, wherein a single chemical entity simultaneously interacts with CB1 receptors and iNOS causing inhibition, as a potential therapeutic strategy for COVID‐19‐related health complications.LINKED ARTICLESThis article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc

Discovery of a novel class of inhaled dual pharmacology muscarinic antagonist and β2 agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD)

The targeting of both the muscarinic and β-adrenergic pathways is a well validated therapeutic approach for the treatment of chronic obstructive pulmonary disease (COPD). In this communication we report our effort to incorporate two pharmacologies into a single chemical entity, whose characteristic must be suitable for a once daily inhaled administration. Contextually, we aimed at a locally acting therapy with limited systemic absorption to minimize side effects. Our lung-tailored design of bifunctional compounds that combine the muscarinic and β-adrenergic pharmacologies by the elaboration of the muscarinic inhibitor 7, successfully led to the potent, pharmacologically balanced muscarinic antagonist and β2 agonist (MABA) 13.