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Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: T.M. and C.B. are founders, executive directors and shareholders of Oryzon Genomics S.A.; C.M., D.R., M.M.P.L., AO, J.S. and E.C. are employees; and A.E., N.G., N.V., M.F., M.M. and J.C.C.P. are former employees of Oryzon Genomics S.A.; I.F. is former member of the SAB of Oryzon Genomics S.A. A.O., M.F., M.M., A.E., N.V, J.C.C.P., T.M., C.M., D.R., C.G.F, M.P., R.N., A.A., are listed as inventors on one or several of the following patent applications of Oryzon Genomics S.A. related to this work: WO2012/013728; WO2013/057320; WO2016/198649; WO2017/158136; WO2019/025588. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This does not alter our adherence to PLOS ONE policies on sharing data and materials with the following exceptions: Polyphemous, proprietary software of Oryzon Genomics S.A., is not available as an exportable .exe code.

The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.

Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.

A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.

In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.

Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.

The human genome encodes five nonpolymorphic major histocompatibility complex class I-like glycoproteins, CD1a to CD1e, that present lipid antigens for specific recognition by T lymphocytes. Using single alkyl chain detergents, we developed a protocol to generate recombinant human CD1b-lipid complexes. We present here the crystal structures of CD1b in complex with either phosphatidylinositol or ganglioside GM2 at 2.3 A and 2.8 A resolutions, respectively. The antigen-binding groove houses four interlinked hydrophobic channels that are occupied by the alkyl chains of the glycolipid plus two detergent molecules. A distinct exit beneath the alpha 2 helix further contributes to the plasticity of the binding groove. These structures reveal the mechanism by which two alkyl chain lipids bind to CD1b, and how CD1b can adapt to ligands of different alkyl chain length. They also suggest how very long alkyl chains, such as those of mycolic acid, could be fully contained within the binding groove. These results extend the spectrum of potential CD1b ligands by revealing that, in addition to two alkyl chain lipids, mono-alkyl and triple-alkyl chain lipids can be accommodated in the binding groove.

2,3-Dehydroneuraminic acid derivative 5 was transformed in five efficient steps into sialyl donor 2, which has a phenylthio group on the beta-side of the 3-position for anchimeric assistance and a diethyl phosphite residue as leaving group at the anomeric carbon. The known GM3 intermediate 10 was transformed into the 4b,4c,8c-O-unprotected acceptor 3, which was then allowed to react with 2 by using TMSOTf as catalyst and acetonitrile as solvent to afford the desired tetrasaccharide 12, which has an alpha(2-8)-linkage between two neuraminic acid residues. Removal of the phenylthio group gave intermediate 13, which was transformed into O-tetraosyl trichloroacetimidate 16 as glycosyl donor. Application of the azidosphingosine glycosylation procedure furnished GD3 (1) in high overall yield. Comparison of synthetic GD3 with bovine-brain-derived GD3 showed that there were similar effects in GD3-triggered uncoupling of mitochondrial respiration and in induction of apoptosis in oligodendrocytes.

D-Glucosamine can be readily transformed into 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino+ ++) -D-glucopyranose (2). From this intermediate valuable glycosyl donors can be obtained; reaction with ethanethiol in the presence of boron trifluoride etherate afforded ethyl 3,4,6-tri-O-acetyl-2-deoxy-1-thio-2-(2,2, 2-trichloroethoxycarbonylamino)-beta-D-glucopyranoside (4) which gave, upon N-acetylation, the N-acetyl-N-trichloroethoxycarbonyl derivative (5). Selective removal of the 1-O-acetyl group in 2 followed by treatment with trichloroacetonitrile in the presence of base afforded 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)- alpha -D-glucopyranosyl trichloroacetimidate (6). Reaction of 5 with five selectively protected glycosides as glycosyl acceptors in the presence of N-iodosuccinimide/trifluoromethanesulfonic acid as the promoter system furnished the corresponding beta-glycosides in good yields, thus exhibiting the valuable glycosyl donor properties of 5. Reductive removal of the trichloroethoxycarbonyl (Teoc) group afforded the corresponding N-acetyl-protected saccharides in high yields. The imidate 6 reacted with three of the above acceptors in the presence of catalytic amounts of trimethylsilyl trifluoromethanesulfonate to give the beta-linked disaccharides in even better yields. The direct replacement of the N-Teoc group by the N-acetyl group using zinc/acetic anhydride, via the free amines as transient intermediates, adds to the high efficiency and convenience of this methodology.