The Past, Present, and Future of Clinically Applied Chimeric Antigen Receptor-T-Cell Therapy.

Immunotherapy represents the fourth pillar of cancer therapy after surgery, chemotherapy, and radiation. Chimeric antigen receptor (CAR)-T-cell therapy is an artificial immune cell therapy applied in clinical practice and is currently indicated for hematological malignancies, with cluster of differentiation 19 (CD19) as its target molecule. In this review, we discuss the past, present, and future of CAR-T-cell therapy. First, we summarize the various clinical trials that were conducted before the clinical application of CD19-targeted CAR-T-cell therapies began. Second, we discuss the accumulated real-world evidence and the barriers associated with applying clinical trials to clinical practices from the perspective of the quality and technical aspects. After providing an overview of all the moving parts involved in the production of CAR-T-cell products, we discuss the characteristics of immune cells (given that T cells are the raw materials for CAR-T-cell therapy) and elucidate the relationship between lifestyle, including diet and exercise, and immune cells. Finally, we briefly highlight future trends in the development of immune cell therapy. These advancements may help position CAR-T-cell therapy as a standard of care.

Stable C-N axial chirality in 1-aryluracil scaffold and differences in in vitro metabolic clearance between atropisomers of PDE4 inhibitor.

We report herein the stable C-N axial chirality in a 1-phenyl-6-aminouracil scaffold owing to the presence of various functional groups at the ortho-position of the N(1)-phenyl group. Racemic 1-phenyl-6-aminouracils were first separated by chiral HPLC or converting them to the corresponding diastereomers using a chiral resolving agent. We then determined the rotational barrier of each atropisomer by a thermal racemization method and found that these compounds have rotational barriers similar to other C-N axially chiral biaryls. In addition, there was a good correlation between the rotational barriers and van der Waals radii of an ortho-substituent of the N(1)-phenyl group. To explore the possibility of the chiral 1-phenyl-6-aminouracil scaffold as a drug lead, we synthesized both atropisomers as phosphodiesterase-4 inhibitors 10. The atropisomers showed significantly different metabolic stabilities while their PDE4 inhibitory activities were somewhat similar. This finding demonstrates the potential utility of stable C-N bond atropisomers in the development of chiral drugs.

Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases.

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.

DSR-71167, a novel mineralocorticoid receptor antagonist with carbonic anhydrase inhibitory activity, separates urinary sodium excretion and serum potassium elevation in rats.

Mineralocorticoid receptor (MR) antagonists, such as spironolactone (SPI) and eplerenone (EPL), are useful for treating hypertension and heart failure. However, these two agents have the serious side effect of hyperkalemia. We hypothesized that adding the ability to inhibit carbonic anhydrase (CA) would reduce the risk of hyperkalemia associated with MR antagonists. We investigated the profiles of DSR-71167 [2-([(2,2-difluoroethyl)amino]methyl)-2'-fluoro-N-(3-methoxy-4-sulfamoylphenyl)biphenyl-4-carboxamide hydrochloride; an MR antagonist with weak CA inhibitory activity] with regard to antimineralocorticoid actions by examining relationships between the urinary excretion of sodium (index of antimineralocorticoid action) in deoxycorticosterone acetate-treated rats and elevation of serum levels of potassium in potassium-loaded rats compared with a DSR-71167 derivative without CA inhibition (2-(hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide), SPI, and EPL. DSR-71167 dose-dependently increased urinary excretion of sodium in deoxycorticosterone acetate-treated rats without elevating serum levels of potassium in potassium-loaded rats. 2-(Hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide, SPI, and EPL elevated serum levels of potassium significantly in potassium-loaded rats at doses that increased MR inhibitory activity. We confirmed that DSR-71167 significantly increases urinary bicarbonate and decreases blood bicarbonate, as pharmacodynamic markers of CA inhibition, in intact rats. Chronic DSR-71167 administration showed antihypertensive effects in high salt-loaded Dahl hypertensive rats. These results demonstrate that DSR-71167 is a novel type of MR antagonist, with CA inhibitory activity, which is expected to become a safer MR antagonist with a low potential risk for hyperkalemia.

Discovery of furan-2-carbohydrazides as orally active glucagon receptor antagonists.

Furan-2-carbohydrazides were found as orally active glucagon receptor antagonists. Starting from the hit compound 5, we successfully determined the structure activity relationships of a series of derivatives obtained by modifying the acidity of the phenol. We identified the ortho-nitrophenol as a good scaffold for glucagon receptor inhibitory activity. Our efforts have led to the discovery of compound 7l as a potent glucagon receptor antagonist with good bioavailability and satisfactory long half-life.

Artificial ladder-shaped polyethers that inhibit maitotoxin-induced Ca2+ influx in rat glioma C6 cells.

Maitotoxin (MTX) is a ladder-shaped polyether produced by the epiphytic dinoflagellate Gambierdiscus toxicus. It is known to elicit potent toxicity against mammals and induce influx of Ca(2+) into cells. An artificial ladder-shaped polyether possessing a 6/7/6/6/7/6/6 heptacyclic ring system, which was designed for elucidating interactions with transmembrane proteins, was found to be the most potent inhibitor against MTX-induced Ca(2+) influx that has ever been reported.

Stereocontrolled synthesis of substituted chiral piperidines via one-pot asymmetric 6π-azaelectrocyclization: asymmetric syntheses of (-)-dendroprimine, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine.

The asymmetric one-pot 6π-azaelectrocyclization of alkenyl vinyl stannane, ethyl (Z)-2-iodo-4-oxobutenoate, and (-)-7-isopropyl-cis-aminoindanol in the presence of a Pd(0) catalyst stereoselectively produced the tetracyclic aminoacetal compounds, resulting from the four-bond formation accompanying by controlling the stereochemistry at the two asymmetric centers. The produced cyclic aminoacetals can be regarded as synthetic precursors of substituted chiral piperidines, and the syntheses of 2,4- and 2,4,6-substituted piperidines were realized from the obtained aminoacetals by the stereoselective hydrogenation of the double bond conjugated with the C-4 ester group and alkylation at the aminoacetal moiety. In addition, the stereoselective synthesis of an indolizidine alkaloid, (-)-dendroprimine, and its three stereoisomers, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine, were achieved.

Convergent synthesis and biological activity of the WXYZA'B'C' ring system of maitotoxin.

The WXYZA'B'C' ring system ( 1) of maitotoxin (MTX) was synthesized in a convergent manner via successive coupling of the W, Z, and C' ring fragments through construction of the XY and A'B' ring systems. The synthetic segment 1 blocked the hemolytic activity elicited by MTX.

Synthesis of 2,4,6-trisubstituted chiral piperidines and (-)-dendroprimine by one-pot asymmetric azaelectrocyclization protocol.

[reaction: see text] Stereocontrolled synthesis of 2,4,6-trisubstituted piperidine diastereomers has been realized from common intermediates, obtained by a one-pot azaelectrocyclization protocol. Based on the method, the asymmetric synthesis of an indolizidine alkaloid, (-)-dendroprimine, was achieved.