Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
Published: April 2011
AI Article Synopsis
Article Abstract
Agonists of somatostatin receptor subtype 2 (sst(2)) have been proposed as therapeutics for the treatment of proliferative diabetic retinopathy and exudative age-related macular degeneration. An HTS screen identified 2-quinolones as weak agonists of sst(2), and these were optimized to provide small molecules with sst(2) binding and functional potency comparable to peptide agonists. Agonist 21 was shown to inhibit rat growth hormone secretion following systemic administration and to inhibit ocular neovascular lesion formation after local administration.
Somatostatin receptor-4 (SST) is a therapeutic target for several conditions, including Alzheimer's disease, seizures, neuropsychiatric disorders, and pain. Our previous work on 1,2,4-triazole derivatives led to enhanced SST binding affinity, selectivity, and functional activity. Herein we report the discovery of 3-thio-1,2,4-triazole series as selective and high affinity SST agonists.
In the current work, we aimed to evaluate the association of clinical data of Cushing's disease (CD) patients with mutation status and to study USP8-related molecular mechanisms connected to the regulation of corticotropinoma growth and activity. 35 CD patients were enrolled; the sequencing of exon 14 in revealed variants in eighteen adenomas, two of which were described for the first time in CD. variants were more common in women (94% vs.
Bitter is one of the five basic taste qualities, along with salty, sour, sweet and umami, used by mammals to access the quality of their food and orient their eating behaviour. Bitter taste detection prevents the ingestion of food potentially contaminated by bitter-tasting toxins. Bitter taste perception is mediated by a family of G protein-coupled receptors (GPCRs) called TAS2Rs.
Purpose: Acromegaly is characterized by an insidious clinical presentation and delayed diagnosis. Longer delays are associated with more comorbidities which can persist after treatment of the growth hormone-secreting pituitary adenoma (GH-PA). Surgery is the primary therapy of GH-secreting PA, which can lead to durable remission.
The term 'fugitive acromegaly' was introduced by the neurosurgeons Bailey and Cushing in 1928 to describe subjects manifesting signs and symptoms of somatotroph hyperfunction with pituitary insufficiency. Currently, it identifies patients with subtle acromegalic dysmorphisms and inconsistent hormonal profile, possibly presenting only with hyperprolactinemia and related clinical symptoms. Patients have rapidly growing, locally invasive, relapsing pituitary macrotumors that can be classified as either acidophil stem cell tumors (ASCTs) or sparsely granulated somatotroph tumors (SGSTs), both of PIT1-lineage.
