6,7-Dihydro-5H-cyclopentadpyrazolo1,5-apyrimidines and their derivatives as novel corticotropin-releasing factor 1 receptor antagonists.
Summary of "6,7-Dihydro-5H-cyclopentadpyrazolo1,5-apyrimidines and their derivatives as novel corticotropin-releasing factor 1 receptor antagonists."
To identify an orally active corticotropin-releasing factor 1 receptor antagonist, a series of 6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives were designed, synthesized and evaluated. An in vitro study followed by in vivo and pharmacokinetic studies of these heterotricyclic compounds led us to the discovery of an orally active CRF1 receptor antagonist. The results of a structure-activity relationship study are presented.
Affiliation
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Journal Details
This article was published in the following journal.
Name: Bioorganic & medicinal chemistry
ISSN: 1464-3391
Pages: 5432-45
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21865047
- DOI: http://dx.doi.org/10.1016/j.bmc.2011.07.055
Medical and Biotech [MESH] Definitions
Receptors, Corticotropin-releasing Hormone
Cell surface proteins that bind corticotropin-releasing hormone with high affinity and trigger intracellular changes which influence the behavior of cells. The corticotropin releasing-hormone receptors on anterior pituitary cells mediate the stimulation of corticotropin release by hypothalamic corticotropin releasing factor. The physiological consequence of activating corticotropin-releasing hormone receptors on central neurons is not well understood.
3,4-dichloro-n-methyl-n-(2-(1-pyrrolidinyl)-cyclohexyl)-benzenea...
A non-peptide, kappa-opioid receptor agonist which has also been found to stimulate the release of adrenocorticotropin (ADRENOCORTICOTROPIC HORMONE) via the release of hypothalamic arginine vasopressin (ARGININE VASOPRESSIN) and CORTICOTROPIN-RELEASING HORMONE. (From J Pharmacol Exp Ther 1997;280(1):416-21)
Corticotropin-releasing Hormone
A peptide of about 41 amino acids that stimulates the release of ADRENOCORTICOTROPIC HORMONE. CRH is synthesized by neurons in the PARAVENTRICULAR NUCLEUS of the HYPOTHALAMUS. After being released into the pituitary portal circulation, CRH stimulates the release of ACTH from the PITUITARY GLAND. CRH can also be synthesized in other tissues, such as PLACENTA; ADRENAL MEDULLA; and TESTIS.
Dihydro-beta-erythroidine
Dihydro analog of beta-erythroidine, which is isolated from the seeds and other plant parts of Erythrina sp. Leguminosae. It is an alkaloid with curarimimetic properties.
Urocortins
Neuropeptides of about 40 amino acids which are structurally similar to CORTICOTROPIN-RELEASING FACTOR. Unlike CRF acting primarily through type 1 CRF RECEPTORS, urocortins signal preferentially through type 2 CRF receptors. Urocortins have wide tissue distribution from fish to mammals, and diverse functions. In mammals, urocortins can suppress food intake, delays gastric emptying, and decreases heat-induced edema.
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