RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1(G93A) transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration

Discovery of Potent and Selective A_2A Antagonists with Efficacy in Animal Models of Parkinson’s Disease and Depression

Adenosine A_2A receptor (A_2AAdoR) antagonism is a nondopaminergic approach to Parkinson’s disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A_2AAdoR antagonists. We herein described a novel series of [1,2,4]­triazolo­[5,1-<i>f</i>]­purin-2-one derivatives that displays functional antagonism of the A_2A receptor with a high degree of selectivity over A₁, A_2B, and A₃ receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound <b>33</b>. Compound <b>33</b> endowed with satisfactory <i>in vitro</i> and <i>in vivo</i> pharmacokinetics properties. Compound <b>33</b> demonstrated robust oral efficacies in two commonly used models of Parkinson’s disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models)

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A_2A Receptor Antagonists and Their Biological Evaluation

Our initial structure–activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound <b>25</b> as a potent and selective A_2A adenosine receptor (A_2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A_2A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability. Compounds <b>41</b> and <b>49</b> demonstrated a number of positive attributes with respect to in vitro ADME properties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound <b>49</b> displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases

Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats

l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits <b>1</b> and <b>2</b> led to the discovery of compounds <b>3</b> and <b>4</b> as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound <b>3</b> or <b>4</b> resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension