Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety.

We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose-dependently induces PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. Compound 2a, bearing a bicyclic aromatic ring, was identified as a novel hPTHR1 agonist during hit to lead modification. It showed moderate PTHR1 agonistic activity with an EC value of 15 μM, and its metabolic stability in human liver microsome (hLM) as well as its solubility in phosphate buffer (PPb) and Fasted state simulated intestinal fluid (FaSSIF) were found to be poor.

Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist.

We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.

Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism.

Parathyroid hormone (PTH) is essential for calcium homeostasis and its action is mediated by the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. Hypoparathyroidism and osteoporosis can be treated with PTH injections; however, no orally effective PTH analogue is available. Here we show that PCO371 is a novel, orally active small molecule that acts as a full agonist of PTHR1.

The pollution and ecological risk of endosulfan in soil of Huai'an city, China.

Endosulfan, a persistent organic pollutant newly listed under the Stockholm Convention, is currently widely produced and used as a pesticide in China. Concentrations of endosulfans (including α-, β-isomers, and their metabolite endosulfan sulfate) were determined in surface soil collected from Huai'an city, where the largest endosulfan producer is located. The concentrations of Σendosulfan (sum of α-endosulfan, β-endosulfan, and endosulfan sulfate) at all sites ranged from 0.

Biological properties of androgen receptor pure antagonist for treatment of castration-resistant prostate cancer: optimization from lead compound to CH5137291.

Background: Castration-resistant prostate cancer (CRPC) is still dependent on androgen receptor (AR) signaling. We previously reported that a novel nonsteroidal AR pure antagonist, CH4933468, which is a thiohydantoin derivative with a sulfonamide side chain, provided in vitro proof of concept but did not in vivo.

Methods: We developed other derivatives, CH5137291, CH5138514, and CH5166623, and their pharmacological properties were compared with CH4933468 and bicalutamide.

Structure-activity relationships of bioisosteric replacement of the carboxylic acid in novel androgen receptor pure antagonists.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of hormone refractory prostate cancer. CH4933468 (32d) with a sulfonamide side chain not only exhibited antagonistic activity with no agonistic activity in the reporter gene assay but also inhibited the growth of bicalutamide-resistant cell lines. This compound also inhibited tumor growth of the LNCaP xenograft in mice dose-dependently.

BDNF-treated retinal progenitor sheets transplanted to degenerate rats: improved restoration of visual function.

The aim of this study was to evaluate the functional efficacy of retinal progenitor cell (RPC) containing sheets with BDNF microspheres following subretinal transplantation in a rat model of retinal degeneration. Sheets of E19 RPCs derived from human placental alkaline phosphatase (hPAP) expressing transgenic rats were coated with poly-lactide-co-glycolide (PLGA) microspheres containing brain-derived neurotrophic factor (BDNF) and transplanted into the subretinal space of S334ter line 3 rhodopsin retinal degenerate rats. Controls received transplants without BDNF or BDNF microspheres alone.

New method for the simultaneous estimation of intrinsic hepatic clearance and protein binding by matrix inhibition.

The purpose of this study was to develop a method for estimating the hepatic clearance (CL(h)) without using a protein binding test. This method allows the simultaneous evaluation of the intrinsic hepatic clearance (CL(int)) with a correction for microsomal binding, and the free fraction in the serum (fu). It uses the decrease in metabolic velocity achieved by decreasing the free fraction of a compound in the incubation mixture (fu(inc)) by the addition of serum, and by changing the microsomal protein concentration.

Visual functional effects of constant blue light in a retinal degenerate rat model.

Retinal degenerative conditions increase susceptibility to light damage, but rapid retinal degeneration (RD) models show less susceptibility to cyclic dim light. We investigated whether constant blue light (BL) exposure can eliminate the residual visual responses in a comparatively rapid RD rat model. Pigmented rhodopsin mutant S334ter line-3 rat pups (21 days old) were exposed for 5-6 consecutive days to constant BL.

Retinal transplants evaluated by optical coherence tomography in photoreceptor degenerate rats.

Optical coherence tomography (OCT), a non-invasive method, was used for qualitative assessment of fetal retinal sheet transplants by non-invasive imaging. Rhodopsin-mutant S334ter-line-3 rats with fast retinal degeneration (28-37-day old) were transplanted with fetal retinal sheets from embryonic day (E) 18-19 pigmented normal rats. Retinal thickness measurements from transplanted (n = 51), no surgery control (n = 8), and normal pigmented rat eyes (n = 6) were obtained using a Zeiss stratus OCT-3 scanning instrument.

Photoreceptor differentiation and integration of retinal progenitor cells transplanted into transgenic rats.

Previous studies evaluating neural stem cells transplanted into the mature retina have demonstrated limited levels of graft-host integration and photoreceptor differentiation. The purpose of this investigation is to enhance photoreceptor cell differentiation and integration of retinal progenitor cells (RPC) following subretinal transplantation into retinal degenerate rats by optimization of isolation, expansion, and transplantation procedures. RPCs were isolated from human placental alkaline phosphatase (hPAP)-positive embryonic day 17 (E17) rat retina and expanded in serum-free defined media.