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Travel Report of A Travel Report 20th RSC-SCI Medicinal Chemistry Symposium (Cambridge, UK) 08-11 September, 2019 Lynette Smyth (AbbVie, Germany) Novel, potent and selective 5-HT2C receptor agonists for the treatment of neurological disorders Items: o 5-HT2C has been indicated in a number of different neurological diseases such as schizophrenia, bipolar disorder and depression and has the potential to be useful in the symptomatic treatment of Alzheimer’s and Parkinson’s disease. The 5-HT2C agonist Locaserin was approved for the treatment of obesity in 2012. It was however shown, at that time, to have poor functional selectivity for 5-HT2C over 5-HT2A and 5-HT2B, leading to a limited tolerated maximal dose. o Therefore, it was desired to investigate new classes of 5-HT2C agonists with improved selectivity. However, the project was terminated due to ‘’strategic’’ reasons. - 1 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report Jean Quancard (Novartis, Switzerland) One binder, two effects. Context dependent inhibition or rescue of MALT1 protease Items: o MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation, making it an attractive target for the treatment of autoimmune diseases. In vivo potency was optimized by 1) reducing clearance with guidance from metabolism identification studies and 2) increasing potency in whole blood by masking a hydrogen bond through intramolecular interaction. However, a patient was identified with a homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. The same allosteric binder can inhibit the wild type enzyme or rescue the MALT1-W580S mutant enzyme. o This suggests that the same drug may be used to treat autoimmune diseases associated with MALT1 activation or to treat combined immunodeficiency in patients with a MALT1 deficiency. - 2 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report James Crawford (Genentech, USA) Resetting the antibacterial arms race: LepB as a novel gram negative target Items: o The arylomycins are a class of antibiotics initially isolated from a soil sample obtained in Cape Coast, Ghana. In this initial isolation, two families of closely related arylomycins, A and B, were identified. We identified the arylomycin class of macrocyclic lipopeptides as a promising starting point based on their inhibition of an essential signal peptidase (SPase) in both Gram-positive and –negative bacteria. Reviewing what was known of their activity, spectrum and resistance profile, we began by attempting to capture interactions lost as a result of the missing P1 residue and simultaneously adding functionality to covalently modify the SPase active site serine. o The optimized arylomycins are unaffected by resistance evolved against therapeutics in current clinical use, and are highly active against 49 strains of multidrug resistant Gram-negative pathogens. Jodi T. Williams (Idorsia, Switzerland) The discovery of the selective orexin1 receptor antagonist (so1ra) act-539313 for the treatment of anxiety disorders Items: o The neuropeptides orexin A (OX-A) and orexin b (OX-B) are synthesized by a small number of neurons in the hypothalamus. Orexin producing neurons project widely to key areas of the brain and are predominantly involved in the control of wakefulness and in the regulation of food intake, reward, addictive behaviors and stress. The OX neuropeptides mediate their effect by stimulating two distinct G-protein coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) that are co-located or selectively located in specific brain areas implying differentiated roles. Antagonism of the OX2 receptor is required to induce sleep, but selective antagonism of the OX1 receptor does not affect sleep. The OX1 receptor is selectively expressed in the bed nucleus of the stria terminalis, amygdala, cingulate cortex and locus coeruleus which paly are role in panic and anxiety. o Both dual orexin receptor antagonists (DORAs) and selective orexin-2 receptor antagonists (SO2RAs) have been shown to promote sleep in rodents and humans. - 3 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report ACT-539313 is currently being prepared for Phase 2. Brock T. Shireman (Janssen, USA) Discovery and disclosure of JNJ-61393215, a selective orexin-1 receptor antagonist Items: o Same as above. U-shape required for all selective OX1 receptor antagonists. - 4 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report Tim Harrison (ALMAC, UK) Ventures in new target space: drugging the DUBs Items: o Deubiquitinating enzymes (DUBs) are proteases that catalyze the de-ubiquitination of protein substrates and as such offer an alternative way to regulate protein homeostasis. Furthermore, since ubiquitination also controls a plethora of regulatory functions beyond direct degradation, inhibition of DUBs provides additional opportunities to manipulate critical cellular processes. o As a result of this dual role in protein degradation and signaling, as well as their increasing linkage to the etiology of numerous pathological conditions including cancer, inflammation and neurodegeneration, DUBs have emerged as a new and attractive target class for the development of First-in-Class medicines with high therapeutic impact. Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl- terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene. Fang Gao (Biogen, USA) The investigation of small molecule inhibitors of PLD for the treatment of ALS Items: o Phospholipase D (PLD) is an enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule phosphatidic acid and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression and is proposed to play a role in neurodegenerative disorders, including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). o Studies at Biogen have demonstrated that knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS. - 5 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report Michael E. Prime (Evotec, UK) Imaging mutant huntingtin aggregates: Development of potential PET ligands Items: o Huntington’s disease (HD) is a rare (prevalence is 1 in 10000 worldwide), fatal, autosomal dominant inherited disease caused by CAG repeat expansion in the huntingtin (HTT) gene, which results in an expanded polyglutamine (polyQ) tract in the mutant huntingtin protein (mHTT). Clinical manifestations of the disease include motor and cognitive impairment, psychiatric disturbances, as well as metabolic abnormalities, with disease onset typically occurring between the ages of 30 and 50, and death 15 to 20 years after onset. Aggregates of mHTT form in brain cells and can be observed by post-mortem analysis. o It is not clear if mHTT aggregates are neuroprotective or neurodegenerative and this question is an area of much controversy and research. There are currently no tools to detect mHTT in vivo. - 6 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report All binding data were obtained using synthetic mHTT fibrils. In addition, CHDI- 00485180 showed binding to human HD post-mortem tissue. FIH evaluation of novel mutant huntingtin PET radioligands [¹¹C]CHDI-00485180-R and [¹¹C]CHDI-00485626. Start Date: 2020-02-01; Completion Date: 2022-02-01 Michael D. Shultz (Novartis, USA) Do we need to change the definition of hit-, lead- and drug-like properties? Items: o Two decades have passed since the rule of five ushered in the concept of "drug-like" properties. Attempts to quantify, correlate, and categorize molecules based on Ro5 parameters evolved into the introduction of efficiency metrics with far reaching consequences in decision making by industry leaders and scientists seeking to discover new medicines. Examination of oral drug parameters approved before and after the original Ro5 analysis demonstrates that some parameters such as clogP and HBD remained constant while the cutoffs for parameters such as molecular weight and HBA have increased substantially over the past 20 years. The time dependent increase in the molecular weight of oral drugs during the past 20 years provides compelling evidence to disprove the hypothesis that molecular weight is a "drug-like" property. This analysis does not validate parameters that have not changed as being "drug-like" but instead calls into question the entire hypothesis that "drug-like" properties exist. For more details see Shultz, M. D. Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs. J Med Chem. 2019, 62, 1701-1714. - 7 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report David J. Edmonds (Pfizer, USA) A potent, orally bioavailable small molecule agonist of the GLP-1 receptor Items: o Glucagon-like peptide-1 (GLP-1) receptor agonists comprise a growing class of agents that deliver unprecedented efficacy in diabetes. Members of the class are also approved or under development for obesity and the class shows further promise for the treatment of non-alcoholic steatohepatitis (NASH). GLP-1 is 30 amino acid peptide hormone that activates the GLP-1 receptor, a class B GPCR that is particularly challenging to stimulate with small molecules.
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