Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references).

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Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

2.5. Ionic Liquids Presented in This Review 2020 3. Cyclocondensation Reactions 2020 4. Synthesis of Three-Membered Heterocycles 2022 4.1. Aziridines 2022 5. Synthesis of Five-Membered Heterocycles 2022 5.1. Pyrroles 2022 5.2. Furans 2022 5.3. Thiophenes 2023 5.4. Pyrazoles 2024 5.5. Imidazoles 2025 5.6. Isoxazoles 2027 5.7. Oxazoles, Oxazolines, and Oxazolidinones 2027 5.8. Thiazoles and Thiazolidinones 2028 6. Synthesis of Six-Membered Heterocycles 2030 6.1. Pyridines 2030 6.2. Quinolines 2031 6.3. Acridines 2033 6.4. Pyrans 2033 6.5. Flavones 2035 6.6. Pyrimidines and Pyrimidinones 2035 6.7. Quinazolines 2037 6.8. -Carbolines 2038 6.9. Dioxanes 2039 6.10. Oxazines 2039 6.11. Benzothiazines 2040 6.12. Triazines 2040 7. Synthesis of Seven-Membered Heterocycles: Diazepines 2041

Ionic liquids in heterocyclic synthesis.

Recent advances in the synthesis of (hetero)aryl-substituted heteroarenes via transition metal-catalysed direct (hetero)arylation of heteroarene C–H bonds with aryl halides or pseudohalides, diaryliodonium salts, and potassium aryltrifluoroborates

The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of hematopoietic cells. These cells are supported by fibroblast-like bone marrow stromal cells, osteoblasts, and osteoclasts which secrete soluble factors and extracellular matrix proteins that mediate these functions. This rich environment serves as a safe haven not only for normal and malignant hematopoietic cells, but also for epithelial tumor cells that metastasize to bone, offering protection from chemotherapeutic agents by common mechanisms. Soluble factors produced in the bone marrow, such as stromal cell-derived factor-1 and interleukin-6, mediate homing, survival, and proliferation of tumor cells, and integrin-mediated adhesion sequesters tumor cells to this protective niche. Environment-mediated drug resistance includes a combination of soluble factors and adhesion, and can be subdivided into soluble factor-mediated drug resistance and cell adhesion-mediated drug resistance. Because it is induced immediately by the microenvironment and is independent of epigenetic or genetic changes caused by the selective pressure of drug exposure, environment-mediated drug resistance is a form of de novo drug resistance. In this form of drug resistance, tumor cells are transiently and reversibly protected from apoptosis induced by both chemotherapy and physiologic mediators of cell death. This protection allows tumor cells to survive the insult of chemotherapy, leading to minimal residual disease, and thereby increases the probability for the development of acquired drug resistance.

https://clincancerres.aacrjournals.org/content/clincanres/14/9/2519.full.pdf

The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance.

Targeted nanoparticles for cancer therapy

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.

Synthesis and SAR of a New Series of COX-2-Selective Inhibitors: Pyrazolo[1,5-a]pyrimidines

The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.

Synthesis and Structure−Activity Relationship of a New Series of COX-2 Selective Inhibitors: 1,5-Diarylimidazoles

The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure−activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating:  bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2‘-(1H-tetrazol-5-yl)-1,1‘-biphenyl-4-yl]methyl]-1H-pyrazole-4-carbo...

Synthesis and Structure−Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

1. Several platelet activating factor (PAF)-antagonists of different chemical structures were tested in the arachidonic acid-, tetradecanoylphorbol acetate-, dithranol-, and benzoic acid-induced mouse ear oedema models. 2. Topical application of UR-10324, UR-11353, CV-6209 and WEB-2086 markedly inhibited ear oedema induced by the four irritants tested, mimicking the profile obtained with dexamethasone. YM-461 was highly effective only in the dithranol-induced ear oedema, while BN-52021 failed to inhibit ear oedema in all models tested. 3. Leukocyte recruitment into the inflamed ears was prevented by PAF-antagonists, as measured by myeloperoxidase activity in the supernatants of ear homogenates. 4. A relationship between PAF-antagonist and anti-inflammatory activities was found in some cases, but other mechanisms cannot be excluded to explain the topical anti-inflammatory effect of these compounds. 5. Our results suggest that topical formulations containing PAF-antagonists could be useful in the treatment of some inflammatory skin diseases and provide evidence on the involvement of PAF in these inflammatory processes.

/pdf/effects-of-paf-antagonists-in-mouse-ear-oedema-induced-by-4ek4i1in81.pdf

Effects of PAF-antagonists in mouse ear oedema induced by several inflammatory agents.

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the α-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the ref...

L. A. Gomez

Papers

Synthesis and SAR of a New Series of COX-2-Selective Inhibitors: Pyrazolo[1,5-a]pyrimidines

Synthesis and Structure−Activity Relationship of a New Series of COX-2 Selective Inhibitors: 1,5-Diarylimidazoles

Synthesis and Structure−Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl)pyrazoles

Effects of PAF-antagonists in mouse ear oedema induced by several inflammatory agents.

Diphenylpropionic Acids as New AT1 Selective Angiotensin II Antagonists