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... calculated physicochemical properties for the macrocyclic drugs with their route of administration reveals that orally administered macrocycles are smaller in size and more lipophilic than parenteral macrocycles, as further indicated by their lower polar surface area (PSA) and fewer hydrogen bond donors (HBDs) (Table 16.1). Interestingly, oral marketed macrocycles display similar lipophilicity to a set (N = 89) of oral small molecule drugs with molecular weight (MW) of >500, lacking a macrocyclic structure (calculated partition coefficient for n-octanol/water (cLogP) mean value 4.4 and 4.2, respectively), thus emphasizing the importance of lipophilicity to cellular absorption processes. ...
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... two sub- classes of the echinocandins and the cyclic peptides with side chain modifications count three members each, while the remaining nine cyclic peptides are spread into six different subclasses. Table 16.1 Calculated physicochemical properties for oral small molecule drugs, different classes of registered macrocycle drugs, and macrocycles in clinical ...
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... but one of the macrocyclic peptide drugs (N = 31) are administered parentally. This set of compounds displays high MW, large PSA, numerous HBD, and low cLogP, providing a clear rationale for why parenteral administration is required (Table 16.1). ...
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... belonging to the glycopeptide subclass are extremely polar, as suggested by their large PSA, numerous HBD, and low cLogP (Table 16.2). All of them are parenterally administered, due to their poor gastro- intestinal absorption. ...
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... vancomycin analogues, dalba- vancin and oritavancin, have been recently approved by the Food and Drug Administration (FDA) for the treat- ment of acute bacterial skin and skin structure infections (ABSSSI). Both of them bear a peripheral hydrophobic group attached to a carbohydrate, reminiscent of natu- rally occurring lipidated sugars (Table 16.2). The long alkyl chains in dalbavancin and telavancin are thought to enhance membrane anchoring and thus their antibiotic activity [36]. ...
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... two highly lipophilic groups of dalbavancin and oritavancin are responsible for hydrophobic interactions with serum proteins (binding = 93 and 85%, respectively), thus con- tributing to their enhanced half-life (t 1/2 ). While vanco- mycin and telavancin have a t 1/2 of 4-6 and 8 h, respectively, dalbavancin's t 1/2 is >14 days, allowing for once weekly dosing, contrary to the at least 2-3 doses per day required for vancomycin and telavancin (Table 16.3) [40][41][42][43][44][45]. ...
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... has been proven effective in various inflammatory skin diseases, such as vitiligo [46], psoriasis [47,48], and seborrheic dermatitis [49]. Tacrolimus possesses a propenyl group in position 8 of the macrolactam and a hydroxyl substituent attached to position 4 of the cyclohexyl moiety, while pimecrolimus possesses, respectively, an ethyl substituent and a chlorine atom (Table 16.4). Despite these similar structures, the two drugs are administered through different routes. ...
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... naphthoquinone-based ansamycin subclass includes three orally administered (rifabutin, rifampicin, rifapentine) and one parenterally delivered (rifaximin) drugs (Table 16.5). Rifaximin, due to its poor oral bioavailability, is used to treat traveler's diarrhea caused by Escherichia coli. ...
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... relies on suppressing the production of the toxic substances in the intestine using the laxative lactu- lose or nonabsorbable antibiotics, such as rifaximin [57]. The rapamycin subclass includes four drugs, two of which are orally administered (Table 16.6). Sirolimus was the first rapamycin macrolide approved by the FDA (1999). ...
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... to approved macrocycles, clinical macrocycles admin- istered orally have higher lipophilicity, as assessed by cLogP, than their parenteral counterparts. Nevertheless, no significant differences in HBDs, PSA, and MW emerged when comparing clinical macrocycles that differ in their mode of administration (Table 16.1). ...
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... administered intranasally, it was temporarily discontinued in 2008 due to the increased blood pressure observed in some patients. It is now in phase III clinical trials for female sexual dysfunction using a subcutaneous administration formulation, and, to date, no significant variations in blood pressure have been registered in treated patients when compared with placebo (Table 16.7) [71][72][73]. ...
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... C virus (HCV) activity: NIM811 1, SCY-635 2, and alisporivir (DEB025) (Table 16.8) [74][75][76]. ...
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... (CB-183, 315; Table 16.9) is a novel oral cyclic lipopeptide now in phase III clinical trials for the treatment of CDAD. Surotomycin works by disrupting the bacterial membrane potential, and in vitro data indi- cate that it is less toxic to gastrointestinal flora than van- comycin. ...
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... eight macrocycles currently in clinical trials belong to the macrolide and ansamycin chemical classes (N = 5 and N = 3, respectively) and are equally distrib- uted between oral and parenteral administration (Figure 16.4b). Due to their structural similarity to other marketed macrocycles, ridaforolimus, solithromycin, rifalazil, rifamycin SV, and retaspimycin represent inter- esting case studies for a better understanding of the influence of structural features on pharmacokinetics (Table 16.10). Ridaforolimus, the dimethylphosphinate analogue of sirolimus (Table 16.6), is undergoing clinical development as an anticancer macrolide, belonging to the subclass of rapamycins. ...
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... to their structural similarity to other marketed macrocycles, ridaforolimus, solithromycin, rifalazil, rifamycin SV, and retaspimycin represent inter- esting case studies for a better understanding of the influence of structural features on pharmacokinetics (Table 16.10). Ridaforolimus, the dimethylphosphinate analogue of sirolimus (Table 16.6), is undergoing clinical development as an anticancer macrolide, belonging to the subclass of rapamycins. The dimethylphosphinate group increases its solubility and allows for both oral and intravenous administration [97,98]. ...
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... is also an oral ansamycin antibiotic, derived from rifamycin SV, which is being developed for the treatment of chlamydia, diarrhea, and tuberculosis. The presence of a benzoxazine ring makes rifalazil more lipophilic than the other orally administered ansamycin drugs (Table 16.5). The high lipophilicity provides good penetration across lipid barriers, thus resulting in high distribution into blood cells, tissues, and organs as proven in both preclinical (rats and dogs) and human studies [103]. ...
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... structures of the new compounds were inspired by the NS3 macrocyclic inhibitor ciluprevir (BILN 2061; Table 16.11), which was halted in clinical development due to cardiac toxicity at high doses in Rhesus monkeys [121][122][123][124][125][126][127][128][129][130]. ...
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... but one (GS-9256) NS3/4a protease inhibi- tor display an acylsulfonamide-linked P1 moiety and dif- fer in terms of hydrophobic P3 side chain, P4 capping group, and P2 heterocyclic substituents. Three of the second-generation inhibitors (grazoprevir [131], simeprevir [132], and paritaprevir [133]) recently received FDA approval for the treatment of chronic genotype 1 HCV infections (Table 16.11). Simeprevir is the only compound of the series bearing a trisubstituted cyclopentane instead of a substituted hydroxyproline as a P2 structural ele- ment. ...
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... paritaprevir can be enhanced by food consumption: relative to fasting conditions, administration of the drug with a moderate-fat meal (approximately 600 kcal; 20-30% calories from fat) or with a high-fat meal (~900 kcal, 60% calories from fat) increases the mean sys- temic exposure by 211 and 180%, respectively [136,137]. While paritaprevir and simeprevir contain an olefin tether connecting the P1 and P3 moieties, grazoprevir (Table 16.11) is a P2-P4 macrocycle bearing an ether- linked quinoxaline P2 moiety and showing potent activ- ity against several HCV genotypes and resistant mutants. Following oral administration, grazoprevir demonstrated moderate bioavailability in rats and dogs (12 and 13%, respectively) but, when tested in HCV-infected chim- panzees, displayed excellent 24 h liver concentration, resulting in good in vivo efficacy [138,139]. ...
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... (5; Table 16.11) is the only NS3/4A protease inhibitor containing a benzyl phosphinic acid moiety at P1 instead of the typical acylsulfonamide group. Compound 5 is the result of SAR studies performed on a series of benzyl phosphinic acid derivatives of ciluprevir in order to increase its permeability and bioavailability. ...
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... and vaniprevir (Table 16.11) both display a carbamate-linked isoindoline moiety at P2, but the mac- rocyclization topology is different: danoprevir possesses a P1-P3 macrocyclization, whereas vaniprevir contains a P2-P4 macrocycle and a saturated P1 side chain. ...
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... (TG-2349; Table 16.11) is a novel, potent, and selective pan-genotypic HCV inhibitor now in phase II clinical trials. Similarly to danoprevir, paritaprevir, and simeprevir, it possesses a P1-P3 macrocycle and is substi- tuted at P2 with a 2-(4-isopropoxyphenyl) [1]benzofuro [3,2d]pyrimidin-4-yl-moiety. ...
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... at Merck, Sharp, and Dohme laboratories recently reported the discovery of the two new NS3/4A protease inhibitors MK-2748 6 and MK-6325 7, which both possess broad genotype (i.e., gt1b, gt3a, gt1b) and mutant (i.e., R155K, A156T, A156V, D168Y) spectrum as well as favorable pharmacokinetic properties (Table 16.11). Compounds 6 and 7 both contain a cyclopentanol carba- mate P2-P4 linker and a methylcyclopropyl acylsulfona- mide at P1. ...
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... (8; Table 16.11) is a macrocyclic indole inhibitor of the HCV NS5B polymerase in multiple phase II clinical trials in combination with simeprevir. TMC647055 was obtained by lead optimization of a 6-carboxylic acid indole via a macrocyclization strategy in order to (i) improve permeability, (ii) increase meta- bolic stability, and (iii) provide inhibitors with superior potency and pharmacokinetic profiles due to the effect of conformational restriction. ...
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... macrocyclic kinase inhibitors, each displaying phys- icochemical properties very similar to oral small mole- cules (e.g., MW < 500, PSA < 140 Å and HBD < 2), are now in different stages of clinical trials (Table 16.12). Pacritinib is a novel selective Janus-associated kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3) inhibitor now in phase III clinical trials for the treatment of myelofibrosis, acute myeloid leukemia (AML), and lymphoma [151,152]. ...
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... recent patient deaths due to cardiac arrest, cardiac failure, and intracranial hemorrhage observed in the patient group exposed to a pacritinib dosing algorithm, induced FDA to place a clinical hold on the drug for myelofibrosis trials [156]. The JAK2, FLT3, and M-CSF (macrophage colony- stimulating factor) kinase inhibitor SB 1578 (9 ; Table 16.12) is the result of an isosteric replacement of one of the phenyl rings of pacritinib with a furan. ...
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... oral bioavailability that resulted was moderate in mice and monkeys (32 and 34%, respec- tively) and poor in rats and dogs (6%) [157][158][159]. The JAK2, FLT3, cyclin-dependent kinase (CDK) inhibitor SB1317/TG02 (10; Table 16.12) has completed phase I clinical trials for the treatment of hematological malig- nancies. ...
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... 10, due to its basic and hydrophobic nature, displays very high permeability in vitro (Caco-2 P app = 28 × 10 −6 cm/s) but low to moderate bioavailability in vivo (3.8, 24, and 37%, respectively, in rats, mice, and dogs) [159,160]. JNJ26483327 (11 ; Table 16.12 is an oral, potent, multi- targeted tyrosine kinase inhibitor in phase I clinical trials in patients with advanced solid tumors. ...
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... humans, 11 is rapidly absorbed after oral administration but not in a dose- proportional relationship [161]. Lorlatinib (PF-06463922) (Table 16.12) is a macrocyclic anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) inhibitor in phase I/II clinical trial for non-small cell lung carcinoma (NSCLC) and associated brain metastasis. It displays broad-spectrum potency, including against resistant mutants, high selectivity and high distribution to the central nervous system (AUC CSF/plasma and AUC brain/plasma 0.31 and 0.21, respectively). ...
Citations
... In this larger size regime (>500 MW), a majority of current macrocyclic drug candidates are natural products or close variants of natural products. 3 Relative to small molecules, there is less flexibility to guide the design of these noncanonical drug candidates to optimize both binding and bioavailability. Studies that further the understanding of macrocyclic peptides and their optimization against biological targets are therefore of great value. ...
... Peptide macrocyclization indeed increases the affinity and selectivity for a specific target, as well as the metabolic stability, permeability and pharmacokinetic properties [71,72]. The current pipeline of macrocycles includes over 80 approved drugs, with almost half of them belonging to the cyclic peptide class [72][73][74]. Among the well-known examples of cyclic peptide drugs on the market, eight currently target GPCRs. ...
The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr11 residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys8 and Trp11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (Ki 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t1/2 > 24 h) compared with NT (t1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED50 = 4.6 µg/kg) and tonic (ED50 = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
... 4 Among their clinical applications as drugs, macrocycles are used in oncology (temsirolimus and 5,6 epothilone B derivatives 7,8 ), as antibiotics (vancomycin, macrolides, and rifampicin), immunology (sirolimus and zotarolimus), and in dermatology (pimecrolimus). 9 Other applications of macrocycles are in supramolecular chemistry (crown ethers, 10 cryptands, catenanes, rotaxanes, 11 and calixarenes). Recently, macrocycles have received growing attention in medicinal chemistry 12−15 because of their unique ability to disrupt protein−protein interactions, 16 improve metabolic stability, 17 and improve cellular permeability by conformational restriction 18−21 resulting in a higher oral bioavailability compared to noncyclic congeners. ...
Macrocycles target proteins that are otherwise considered undruggable because of a lack of hydrophobic cavities and the presence of extended featureless surfaces. Increasing efforts by computational chemists have developed effective software to overcome the restrictions of torsional and conformational freedom that arise as a consequence of macrocyclization. Moloc is an efficient algorithm, with an emphasis on high interactivity, and has been constantly updated since 1986 by drug designers and crystallographers of the Roche biostructural community. In this work, we have benchmarked the shape-guided algorithm using a dataset of 208 macrocycles, carefully selected on the basis of structural complexity. We have quantified the accuracy, diversity, speed, exhaustiveness, and sampling efficiency in an automated fashion and we compared them with four commercial (Prime, MacroModel, molecular operating environment, and molecular dynamics) and four open-access (experimental-torsion distance geometry with additional “basic knowledge” alone and with Merck molecular force field minimization or universal force field minimization, Cambridge Crystallographic Data Centre conformer generator, and conformator) packages. With three-quarters of the database processed below the threshold of high ring accuracy, Moloc was identified as having the highest sampling efficiency and exhaustiveness without producing thousands of conformations, random ring splitting into two half-loops, and possibility to interactively produce globular or flat conformations with diversity similar to Prime, MacroModel, and molecular dynamics. The algorithm and the Python scripts for full automatization of these parameters are freely available for academic use.
... Folding through cyclisation helps to bury some peptide polarity in the interior of the macrocycle making its exterior surface less polar, more hydrophobic, and consequently more permeable through lipid membranes [193]. These and other advantages have led to approval of ~40 macrocyclic peptide drugs (Table VI), with many other macrocyclic peptides in clinical trials or in development [194,195]. Nevertheless, like almost all linear peptides, most cyclic peptides are not particularly membrane permeable; only a few are absorbed from the intestine, and even fewer have sufficient oral bioavailability to be effective by the oral route [193]. Here, we summarise examples of orally-administered cyclic peptides, as distinct from other macrocycles [196], and point to some observations on these and model cyclic peptides that may help lead to improvements in cyclic peptides as oral drugs. ...
... Cyclic peptide drugs have been approved for clinical use in a number of disease settings [195,197,198] (Table VI), with bacterial and fungal infections, diabetes, and cancer being most common [193,194,[197][198][199]. Most cyclic peptide drugs are delivered by injection, with very few used orally due to the issues raised in this review (Fig. 6). ...
... Selected cyclic peptides that have progressed to clinical trials or are in development are shown in Table VII [194,195,218]. Most have only low oral bioavailability due to high polarity, flexibility, or charged amines/carboxylates that all promote solvation by water. ...
In its 33 years, ADDR has published regularly on the potential of oral delivery of biologics especially peptides and proteins. In the intervening period, analysis of the preclinical and clinical trial failures of many purported platform technologies has led to reflection on the true status of the field and reigning in of expectations. Oral formulations of semaglutide, octreotide, and salmon calcitonin have completed Phase III trials, with oral semaglutide being approved by the FDA in 2019. The progress made with oral peptide formulations based on traditional permeation enhancers is against a background of low oral and variable bioavailability values of ~1%, leading to a current perception that only potent peptides with a viable cost of synthesis can be realistically considered. Desirable features of candidates should include a large therapeutic index, some stability in the GI tract, a long elimination half-life, and a relatively low clearance rate. Administration in nanoparticle formats have largely disappointed, with few prototypes reaching clinical trials: insufficient particle loading, lack of controlled release, low epithelial particle uptake, and lack of scalable synthesis are being the main reasons for discontinuation. Disruptive technologies based on engineered devices promise improvements, but scale-up and toxicology aspects are issues to address. In parallel, medicinal chemists are synthesizing stable hydrophobic macrocyclic candidate peptides of lower molecular weight with potential for greater oral bioavailability than linear peptides, but without a requirement for elaborate drug delivery systems. In summary, while there have been advances in understanding the limitations of peptides for oral delivery, low membrane permeability, metabolism, and high clearance rates continue to hamper progress.
RNA molecules both contribute to and are causative of many human diseases. One method to perturb RNA function is to target its structure with small molecules. However, discovering bioactive ligands for RNA targets is challenging. Here, we show that the bioactivity of a linear dimeric ligand that inactivates the RNA trinucleotide repeat expansion that causes myotonic dystrophy type 1 [DM1; r(CUG)exp] can be improved by macrocyclization. Indeed, the macrocyclic compound is ten times more potent than the linear compound for improving DM1‐associated defects in cells, including in patient‐derived myotubes (muscle cells). This enhancement in potency is due to the macrocycle's increased affinity and selectively for the target, which inhibit r(CUG)exp’s toxic interaction with muscleblind‐like 1 (MBNL1), and its superior cell permeability. Macrocyclization could prove to be an effective way to enhance the bioactivity of modularly assembled ligands targeting RNA.
