Aim: Parathyroid hormone-1 receptor (PTH1R) is a member of B G protein-coupled receptors. The agonistic activation of the PTH1R results in the production and secretion of osteoclast-stimulating cytokines while antagonists may be used to treat bone metastases, hypercalcemia, cachexia and hyperparathyroidism. Results: We built pharmacophore models and investigated the characteristics of PTH1R agonists and antagonists. The agonist model consists of three hydrophobic points, one hydrogen bond acceptor and one positive ionizable point. The antagonist model consists of one hydrogen bond donor and three hydrophobic points. Conclusion: The features of the two models are similar, but the hydrogen bond acceptor, which is the main difference between PTH1R agonists and antagonists, suggests it may be essential for the agonist.

2018-10-01·American Journal of Physiology-Renal Physiology3区 · 医学

Modulation of mean arterial pressure and diuresis by renomedullary infusion of a selective inhibitor of fatty acid amide hydrolase

3区 · 医学

Article

作者: Dempsey, Sara K. ; Daneva, Zdravka ; Poklis, Justin L. ; Ritter, Joseph K. ; Li, Ningjun ; Ahmad, Ashfaq ; Li, Pin-Lan

The kidneys contribute to the control of body fluid and electrolytes and the long-term regulation of blood pressure through various systems, including the endocannabinoid system. Previously, we showed that inhibition of the two major endocannabinoid-hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, in the renal medulla increased the rate of urine excretion (UV) and salt excretion without affecting mean arterial pressure (MAP). The present study evaluated the effects of a selective FAAH inhibitor, N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidine carboxamide (PF-3845) on MAP and renal functions. Infusion of PF-3845 into the renal medulla of C57BL/6J mice reduced MAP during the posttreatment phases and increased UV at 15 and 30 nmol/min per gram kidney weight (g kwt), relative to the pretreatment control phase. Intravenous PF-3845 administration reduced MAP at the 7.5, 15, and 30 doses and increased UV at the 15 and 30 nmol⋅min−1⋅g−1 kwt doses. PF-3845 treatment elevated sodium and potassium urinary excretion and medullary blood flow. Homozygous FAAH knockout mice were refractory to intramedullary PF-3845-induced changes in MAP, but UV was increased. Both MAP and UV responses to intramedullary PF-3845 in C57BL/6J mice were diminished by pretreatment with the cannabinoid type 1 receptor-selective antagonist, rimonabant (3 mg/kg, ip) but not the cyclooxygenase 2-selective inhibitor, celecoxib (15 mg/kg, iv). Liquid chromatography-tandem mass spectrometry analyses showed increased anandamide in kidney tissue and 2-arachidonoyl glycerol in plasma after intramedullary PF-3845. These data suggest that inhibition of FAAH in the renal medulla leads to both a diuretic and blood pressure-lowering response mediated by elevated anandamide in kidney tissue or 2-arachidonoyl glycerol in plasma.

2018-01-01·Bone & Joint Research2区 · 医学

Parathyroid hormone-related protein exhibits antioxidant features in osteoblastic cells through its N-terminal and osteostatin domains

2区 · 医学

ArticleOA

作者: De la Fuente, M. ; Ardura, J. A. ; Martínez de Toda, I. ; Largo, R. ; Portal-Núñez, S. ; Herrero-Beaumont, G. ; Esbrit, P. ; Lozano, D.

Objectives Oxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (PTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The PTH counterpart in bone, which is the PTH-related protein (PTHrP), displays osteogenic actions through both its N-terminal PTH-like region and the C-terminal domain. Methods We examined and compared the antioxidant capacity of PTHrP (1-37) with the C-terminal PTHrP domain comprising the 107-111 epitope (osteostatin) in both murine osteoblastic MC3T3-E1 cells and primary human osteoblastic cells. Results We showed that both N- and C-terminal PTHrP peptides at 100 nM decreased reactive oxygen species production and forkhead box protein O activation following hydrogen peroxide (H2O2)-induced oxidation, which was related to decreased lipid oxidative damage and caspase-3 activation in these cells. This was associated with their ability to restore the deleterious effects of H2O2 on cell growth and alkaline phosphatase activity, as well as on the expression of various osteoblast differentiation genes. The addition of Rp-cyclic 3′,5′-hydrogen phosphorothioate adenosine triethylammonium salt (a cyclic 3',5'-adenosine monophosphate antagonist) and calphostin C (a protein kinase C inhibitor), or a PTH type 1 receptor antagonist, abrogated the effects of N-terminal PTHrP, whereas protein phosphatase 1 (an Src kinase activity inhibitor), SU1498 (a vascular endothelial growth factor receptor 2 inhibitor), or an anti osteostatin antiserum, inhibited the effects of C-terminal PTHrP. Conclusion These findings indicate that the antioxidant properties of PTHrP act through its N- and C-terminal domains and provide novel insights into the osteogenic action of PTHrP. Cite this article: S. Portal-Núñez, J. A. Ardura, D. Lozano, I. Martínez de Toda, M. De la Fuente, G. Herrero-Beaumont, R. Largo, P. Esbrit. Parathyroid hormone-related protein exhibits antioxidant features in osteoblastic cells through its N-terminal and osteostatin domains. Bone Joint Res 2018;7:58–68. DOI: 10.1302/2046-3758.71.BJR-2016-0242.R2.

项与 Parathyroid Hormone Receptor Type-1 Antagonist(Crinetics Pharmaceuticals) 相关的新闻（医药）

2022-06-08

·BioSpace

Crinetics Presents Clinical and Research Results at ENDO 2022CRN04894 Selected for Oral Presentation

SAN DIEGO, June 08, 2022 (GLOBE NEWSWIRE) -- Crinetics Pharmaceuticals Inc. (Nasdaq: CRNX) announced that results from the company’s Phase 1 study of CRN04894, the company’s investigational candidate for the treatment of Cushing’s disease, congenital adrenal hyperplasia (CAH) and other conditions driven by excess adrenocorticotropic hormone (ACTH), were selected for an oral presentation at ENDO 2022, the Endocrine Society’s annual meeting. Crinetics recently reported that administration of CRN04894 reduced both serum cortisol levels and 24-hour urine free cortisol excretion in the presence of sustained, disease-like ACTH concentrations in multiple-ascending dose cohorts of a Phase 1 study. Results from the company’s Phase 1 study of CRN04777, the company’s investigational candidate for the treatment of congenital hyperinsulinism (HI) will be presented as a narrated “Poster Plus.” A late-breaking Poster Plus will also be presented on the company’s preclinical-stage parathyroid hormone (PTH) antagonist for the treatment of hypercalcemia. Poster Plus presenters will participate in Meet-and-Greet sessions and their posters will be accompanied by 5-minute videos for attendees. Presentation details: Title: (OR12) Inhibition of Basal and ACTH-Stimulated Cortisol Secretion in Humans Using an Oral, Nonpeptide ACTH Antagonist (CRN04894) Time: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m. ET Location: Oral Session; A404-A405 Title: (PSUN304) CRN04777, an Oral, Nonpeptide SST5-selective Somatostatin Agonist Dose Dependently Suppresses Basal and Stimulated Insulin Secretion Time: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m. ET Location: Poster+ Session; Hall A1 Title: (LBSAT142) Discovery and Characterization of a Potent and Orally Bioavailable Parathyroid Hormone Receptor Type-1 (PTHR1) Antagonist for the Treatment of Hypercalcemia Time: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m. ET Location: Poster+ Session; Hall A1 The posters and oral presentations will be made available on the Crinetics website in accordance with the congress’ embargo policy. For attendees of ENDO 2022, Crinetics staff will be available to address questions and discuss pipeline programs at the company booth (#822) and in the virtual exhibit hall. About Crinetics Pharmaceuticals Crinetics Pharmaceuticals is a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors. Paltusotine, a somatostatin receptor type 2 (SST2) agonist, is in Phase 3 clinical development for acromegaly and Phase 2 clinical development for carcinoid syndrome associated with neuroendocrine tumors. Crinetics has demonstrated pharmacologic proof-of-concept in Phase 1 clinical studies for CRN04777, a somatostatin receptor type 5 (SST5) agonist for congenital hyperinsulinism, and CRN04894, an ACTH antagonist for the treatment of Cushing’s disease, congenital adrenal hyperplasia, and other diseases of excess ACTH. All of the company’s drug candidates are orally delivered, small molecule new chemical entities resulting from in-house drug discovery efforts. Contacts: Chas Schultz VP, IR & Corporate Communications cschultz@crinetics.com (858) 450-6464 Investors / Media: Corey Davis LifeSci Advisors, LLC cdavis@lifesciadvisors.com (212) 915-2577 Aline Sherwood Scienta Communications asherwood@scientapr.com (312) 238-8957

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