thienotriazolodiazepine (RO 111464) / Roche, Novartis - LARVOL DELTA

A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways. (PubMed, Cell Death Dis) - "(+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F-actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL-stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment."

Journal • Osteoporosis • Rheumatology • BRD4

Brotizolam During Pregnancy and Lactation: Brotizolam Levels in Maternal Serum, Cord Blood, Breast Milk, and Neonatal Serum. (PubMed, Breastfeed Med) - "Brotizolam is a sedative-hypnotic thienotriazolodiazepine that is a benzodiazepine analog used for debilitating insomnia...A 28-year-old woman diagnosed with bipolar II disorder received brotizolam during pregnancy (28-40 weeks' gestational age) and lactation, along with sertraline, alprazolam, and trazodone...Brotizolam transfer into placenta and breast milk was negligible. Further studies should assess the safety of brotizolam in fetuses and breastfed infants."

Journal • Bipolar Disorder • CNS Disorders • Depression • Insomnia • Mood Disorders • Movement Disorders • Psychiatry • Respiratory Diseases • Sleep Disorder

A Case Series of Etizolam in Opioid Related Deaths. (PubMed, J Anal Toxicol) - "Etizolam is a novel psychoactive substance and novel benzodiazepine of the thienotriazolodiazepine class that has recently seen an increasing trend in use worldwide...Etizolam use continues to be observed and poses as a potentially lethal contribution to multiple drug toxicity, especially in the age of the opioid crisis. Assessment of analytes like etizolam require up-to-date methodologies and vigilance in testing to better characterize the toxicology and interpret the contribution to death."

Clinical • Journal • Cardiovascular • Pain • Respiratory Diseases

The thienotriazolodiazepine Ro 11-1464 increases plasma apoA-I and promotes reverse cholesterol transport in human apoA-I transgenic mice (Br J Pharmacol) - Ro 11-1464 causes increased hepatic expression & plasma levels of apoA-I & a suppression of LCAT & a marked enhancement of reverse cholesterol transport, but also some symptoms of liver toxicity; The compound may therefore be a prototype for a next generation of anti-atherosclerotic medicines

Preclinical • Dyslipidemia

Synthetic Lethality of DHFR Inhibition in Combination with BRD4/MYC Blockade in Pancreatic Ductal Adenocarcinoma Cells (PDAC) (ASTRO 2019) - "Methotrexate (MTX) is a chemotherapy agent used in a variety of cancers by inhibiting DHFR, an enzyme that participates in the tetrahydrofolate (THF) synthesis and one carbon unit formation. JQ-1 is a thienotriazolodiazepine and a potent inhibitor of BRD4/MYC pathway, which can be a promising chemoprevention drug in the future... Our results indicated that the combination of DHFR inhibitor MTX and BRD4/MYC inhibitor JQ-1 could induce synthetic lethality in pancreatic cancer both in vitro and in vivo, by disturbing nucleotide biosynthesis pathways. This study may provide us with a promising strategy by using MTX and JQ-1, to increase the efficacy of chemotherapy of pancreatic cancer."

Combination therapy

Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy. (PubMed, Future Sci OA) - "Consequently, following the demonstration that thienotriazolodiazepine small molecules effectively inhibit BET, clinical trials were initiated. We thus discuss the mechanisms of action of various BET inhibitors and the prospects for their clinical use as cancer therapeutics."

Journal • Review