- LipE guided discovery of isopropylphenyl pyridazines as pantothenate kinase modulators
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Pantothenate kinase (PANK) is the critical regulator of intracellular levels of coenzyme A and has emerged as an attractive target for treating neurological and metabolic disorders. This report describes the optimization, synthesis, and full structure–activity relationships of a new chemical series of pantothenate competitive PANK inhibitors. Potent drug-like molecules were obtained by optimizing a high throughput screening hit, using lipophilic ligand efficiency (LipE) derived from human PANK3 IC50 values to guide ligand development. X-ray crystal structures of PANK3 with index inhibitors from the optimization were determined to rationalize the emerging structure activity relationships. The analysis revealed a key bidentate hydrogen bonding interaction between pyridazine and R306′ as a major contributor to the LipE gain observed in the optimization. A tractable series of PANK3 modulators with nanomolar potency, excellent LipE values, desirable physicochemical properties, and a well-defined structural binding mode was produced from this study.
- Sharma, Lalit Kumar,Yun, Mi Kyung,Subramanian, Chitra,Tangallapally, Rajendra,Jackowski, Suzanne,Rock, Charles O.,White, Stephen W.,Lee, Richard E.
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- OGA INHIBITOR COMPOUNDS
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The present invention relates to O-GlcNAc hydrolase (OGA) inhibitors. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which inhibition of OGA is beneficial, such as tauopathies, in particular Alzheimer's disease or progressive supranuclear palsy; and neurodegenerative diseases accompanied by a tau pathology, in particular amyotrophic lateral sclerosis or frontotemporal lobe dementia caused by C9ORF72 mutations; or alpha synucleinopathies, in particular Parkinson's disease, dementia due to Parkinson's (or neurocognitive disorder due to Parkinson's disease), dementia with Lewy bodies, multiple system atrophy, or alpha synucleinopathy caused by Gaucher's disease.
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Page/Page column 61; 64
(2021/06/26)
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- Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-methylpiperazin-1- yl]nicotinonitriles as active-site inhibitors of sphingosine 1-phosphate lyase for the treatment of multiple sclerosis
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Sphingosine 1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the cocrystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases.
- Weiler, Sven,Braendlin, Nadine,Beerli, Christian,Bergsdorf, Christian,Schubart, Anna,Srinivas, Honnappa,Oberhauser, Berndt,Billich, Andreas
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p. 5074 - 5084
(2014/07/08)
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- IMIDAZOLE DERIVATIVES
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Described herein are compounds of formula (I), formula la or formula lb The compounds of formula I, formula la or formula lb act as DGATl inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
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Page/Page column 38
(2012/05/31)
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- OCTAHYDRO-PYRROLO[3,4-B]PYRROLE DERIVATIVES
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Octahydro-pyrrolo[3,4-b]pyrrole derivatives are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Octahydro-pyrrolo[3,4-b]pyrrole compounds, methods for using such compounds, compositions for making th
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Page/Page column 93-94
(2008/06/13)
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- Carboxylic acid derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
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The invention relates to carboxylic acid derivatives of general formula wherein A to G are defined as in claim 1, the tautomers thereof, the stereoisomers thereof including the mixtures thereof and the addition salts thereof, particularly the physiologically acceptable salts with inorganic or organic acids or bases, which have valuable pharmacological properties, preferably inhibitory effects on aggregation, and to pharmaceutical compositions containing the compounds and processes for preparing them.
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