Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones <b>9b</b>, <b>9i</b>–<b>9am</b>. Many of these hydroxyisoindolinones are converted to chlorophthalazines <b>1b</b>–<b>1v</b> via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to <i>N</i>,<i>N</i>-dimethylaminophthalimide (<b>8a</b>) provided dihydrobenzoazepinediones <b>15a</b>–<b>15c</b> via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids <b>16a</b>–<b>16d</b> and 2-pyrazolyl benzohydrazides <b>17a</b>–<b>17g</b> rather than the expected alkynyl phthalazinones

Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity

There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo target coverage has been challenging. Here we describe the optimization of a potent, selective series of quinazolinone-based TRPA1 antagonists. High-throughput screening identified <b>4</b>, which possessed promising potency and selectivity. A strategy focused on optimizing potency while increasing polarity in order to improve intrinisic clearance culminated with the discovery of purinone <b>27</b> (AM-0902), which is a potent, selective antagonist of TRPA1 with pharmacokinetic properties allowing for >30-fold coverage of the rat TRPA1 IC₅₀ in vivo. Compound <b>27</b> demonstrated dose-dependent inhibition of AITC-induced flinching in rats, validating its utility as a tool for interrogating the role of TRPA1 in in vivo pain models