Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We identified a series of structurally novel SCD (Delta9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC(50) value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Delta5 and Delta6 desaturases.
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PMID:Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors. 1924 3

We discovered a structurally novel SCD (Delta9 desaturase) inhibitor 4a (CVT-11,563) that has 119 nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Delta5 and Delta6 desaturases. This compound has 90% oral bioavailability (rat) and excellent plasma exposure (dAUC 935 ng h/mL). Additionally, 4a shows moderately selective liver distribution (three times vs plasma and adipose tissue) and relatively low brain penetration. In a five-day study (high sucrose diet, rat) compound 4a significantly reduced SCD activity as determined by GC analysis of fatty acid composition in plasma and liver. We describe the discovery of 4a from HTS hit 1 followed by scaffold replacement and SAR studies focused on DMPK properties.
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PMID:Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors. 1939 19

The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC(50) in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration.
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PMID:Novel and potent inhibitors of stearoyl-CoA desaturase-1. Part II: Identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide and its biological evaluation. 1954 82

Beta-hemoglobinopathies such as sickle cell disease represent a major global unmet medical need. De-repression of fetal hemoglobin in erythrocytes is a clinically validated approach for the management of sickle cell disease, but the only FDA-approved medicine for this purpose has limitations to its use. We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules with the ability to de-repress fetal hemoglobin, which resulted in the identification of the benzoxaborole-containing hit compound 1. This compound was found to have modest cellular potency and lead-like pharmacokinetics, but no identifiable SAR to enable optimization. Systematic deconstruction of a closely related analog of 1 revealed the fragment-like carboxylic acid 12, which was then optimized to provide tetrazole 31, which had approximately 100-fold improved cellular potency compared to 1, high levels of oral exposure in rats, and excellent solubility.
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PMID:A hit deconstruction approach for the discovery of fetal hemoglobin inducers. 3055 30

A look into the associations of socioeconomic status (SES) with prevalence of various complications in sickle cell disease (SCD) is necessary, for an improvement of societal norms, governmental health policies and strategies. We therefore studied the influence of SES indices on certain hematological and clinical parameters in children with SCD in Saudi Arabia. We included 32 female and 33 male patients aged 5-16 years, who were classified based upon their family income. Family monthly income was divided into 4 categories from lowest to highest, with socioeconomic class1 having low earnings of <5000 SAR; the middle income class divided further into class 2 with earnings >5000-10,000 SAR, and class 3 with earnings >10,000-15,000 SAR; and the higher income class 4 with earnings of >15,000 SAR. The assessment indices used were, the frequency of vaso-occlusive crisis (VOC), adverse events, and hematological parameters. A higher percentage of children affected with the disease were from class1, which is the low socio-economic class. It was found that the percentage of frequency of VOC pain crisis, and adverse events was higher in social class 1 patients than in the classes 2, 3, and 4. Also, the age group 5-10 years appeared more susceptible to adverse events and VOC. Our findings suggest the need to conduct future larger studies, to deduce the modifying influence of disparity in SES on certain clinical and hematological indices in children with SCD.
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PMID:Socioeconomic status dependent medical complexities in children with sickle cell disease in Saudi Arabia. 3256 96