Cerebral creatine (Cr) deficiency syndromes are caused by AGAT, GAMT or SLC6A8 deficiencies that may cause severe neurodevelopmental delay and intellectual disability.
Researchers from Centre National de la Recherche Scientifique and affiliated organizations presented the discovery and preclinical identification of novel inhibitors of metallo-beta-lactamases (MBLs). Synthesis and optimization of novel broad-spectrum inhibitors against most relevant MBLs, such as VIM-type enzymes and NDM-1, led to the identification of JMV-7061 as the lead from the series.
Microsomal prostaglandin E2 synthase-1 (mPGES1) is a molecule belonging to the MAPEG superfamily and is involved in the conversion of PGH2 to excess PGE2 associated with pain and inflammation. Gesynta Pharma AB presented first data on the mPGES1 inhibitor GS-248 for the treatment of pain and inflammation. In their experiments, GS-248 demonstrated a human whole-blood assay (hWBA) IC50 of 0.4 nM, and hWBA activity about 1000-fold more potent than that of celecoxib. No cross reactivity was observed with COX1 or COX2. Moreover, the compound showed IC50 values for human, dog, rat/mouse and minipig mPGES1 of 2.5, 1.3, > 1000 and 23 nM, respectively.
Previous research has demonstrated that the expression of the calcium-activated potassium channel (Kca 3.1) is higher in patients with idiopathic pulmonary fibrosis (IPF), and that genetic and pharmacological inhibition of Kca3.1 was able to prevent or attenuate fibrosis.
Dysregulation of complement activation plays a key role in the pathophysiology of several diseases, which makes it an attractive therapeutic target. C3 has an important role and central position within the signaling cascade, and is a potential target for therapy.
Argininosuccinic aciduria (ASA) is a disorder caused by argininosuccinate lyase (ASL) deficiency and is the second most common inherited urea cycle defect.
Investigators described preclinical data for AZD-5462 (Astrazeneca plc/Mitsubishi Tanabe Pharma Corp.), a novel oral agonist of the relaxin family peptide receptor 1 (RXFP1), being developed for the treatment of cardiorenal disease.
Molecure SA presented data on the discovery of the clinical candidate OATD-02, a first-in-class, highly potent dual arginase-1/2 (ARG1/2) inhibitor with excellent activity against intracellular ARG2, thereby holding promise as an immunotherapeutic for cancer.
Efforts at Abbvie Inc. to selectively target voltage-gated sodium channel subunit alpha Nav1.7 to treat pain led to the discovery of quinoline and quinolone agents and, through structure-activity relationship studies, the candidate product ABBV-318. While Nav1.7 potency could be achieved with earlier compounds, efforts were required to improve characteristics including hERG activity, pharmacokinetics and selectivity over Nav1.5, yielding compounds which blocked Nav1.7 as well as another target for treating pain, Nav1.8.
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