An Open Label, Single Center, Adaptive Phase I Study in Healthy Volunteers, to Evaluate the Safety, Efficacy and Dose Responses of SB-751689 (Ronacaleret; a Calcium Sensing Receptor Antagonist)

The present study aims to evaluate the impact of 5 days oral administration of ronacaleret 100 miligram (mg) and 400 mg on changes in circulating CD34+ cells, when ronacaleret is followed by the administration of a single dose of plerixafor in healthy human volunteers.
This single centre adaptive design study will be carried out in 2 parts. The part A will evaluate the change in peripheral circulating CD34+ cells in response to two different 5 day regimens of ronacaleret (100 mg or 400 mg once daily), given in conjunction with a single dose of plerixafor (0.24 mg/kilogram [kg]) sub-cutaneously (SC) on the evening of the final days dosing approximately 12 hours before collection of CD34+ cells on day 6. Subjects (5 each) will be assigned to either one of the ronacaleret arms, in an open fashion. Comparisons will be made in the change from baseline to end of treatment peripheral CD34+ cell counts. Part A will be conducted in two cohorts with 5 subjects being enrolled into each of the 2 treatment arms making up the first cohort. Cohort 2 will involve up to 5 further subjects being enrolled into each treatment arm.
The structure of part B will be finalized following a review of data generated in part A.
The total study duration of Part A for each subject including the screening, treatment and follow-up periods will be approximately 7 weeks.

开始日期2012-11-02

申办/合作机构

GSK Plc

NCT01466335

/ Completed临床1期

A Randomized, Double Blind, Parallel Group, Single Center, Adaptive Phase I Study to Evaluate the Safety, Efficacy and Dose Responses of SB-751689 (Ronacaleret; a Calcium Sensing Receptor Antagonist) for Durations Not to Exceed 28 Days, Versusplacebo in Healthy Human Volunteers.

Ronacaleret is an orally administered CaSR antagonist which has previously been demonstrated to transiently increase PTH in both animals and humans. Additional studies in post-menopausal women and patients with distal radial fractures have demonstrated both anabolic and catabolic effects on bone biomarkers and scans of bone density. Based on ronacalerets ability to interact with the CaSR inducing PTH release and activating endogenous bone metabolism of both osteoblasts and osteoclasts, it is our intention to evaluate the impact activation of this pathway has on mobilization of Hematopoietic stem cell (HSCs) into the periphery.
This is an adaptive, phase I, randomized, single centre, double-blind dose finding, parallel-group, multi-cohort placebo controlled study of the efficacy and safety of ronacaleret in up to 45 healthy human volunteers. Cohorts of eligible subjects will be studied for periods up to 28 days. Total daily doses of ronacaleret will range from 100mg, up to 400mg and be administered for a maximum of 28days. The first part of this study will evaluate several doses and schedules of ronacaleret, run in parallel, with respect to their ability to affect mobilization of CD34+ cells into the peripheral circulation. In subsequent cohorts of the study we will utilize information obtained from previous cohorts to further refine and optimise those dosing paradigms which show efficacy. For the first cohort of study participants; the study will commence with 6 days of dosing in an inpatient setting followed by 21 days of continued dosing and evaluation as an outpatient, with a series of regularly scheduled visits, with the final visit on day 28. The study period will include evaluations of pharmacokinetic and pharmacodynamic parameters along with standard laboratory and safety evaluations. The second cohort may be treated with ronacaleret for periods ranging from 14 to 28 days in order to optimise the treatment paradigm with respect to pharmacodynamic efficacy. The PK/PD of each group in cohort one will be utilized to make adjustments in the total daily dose, dose frequency and or duration of dosing investigated in cohort 2. Decisions will be made as to dropping doses based on the PK/PD results and any safety considerations. An initial equal randomization amongst groups within the first cohort may be adjusted to allow for other randomization strategies as various doses and schedules are assessed.
The objective of this study is to characterise the dose-response curve for ronacaleret with respect to safety and efficacy based on changes in peripheral CD34+ cell counts. Results obtained from this study will inform us: of optimized doses, schedules, and durations of treatment for future studies. Additional cohorts may be added to further explore the dose schedule and duration if required. The exact number of cohorts studied will depend on the results obtain from the prior groups and the desire to explore a variety of doses and schedules. The aims of the present study (CR9115166) include an assessment of the pharmacodynamic effects (mobilization of CD34+ cells), safety, tolerability, and pharmacokinetics of ronacaleret in healthy human volunteers.

开始日期2011-10-27

申办/合作机构

GSK Plc

EUCTR2007-001477-29-CZ

/ Not yet recruitingN/A

A proof-of-concept study of SB-751689 in male and female subjects with a fractured distal radius.

开始日期2008-04-17

申办/合作机构-

100 项与 Ronacaleret Hydrochloride 相关的临床结果

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100 项与 Ronacaleret Hydrochloride 相关的转化医学

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100 项与 Ronacaleret Hydrochloride 相关的专利（医药）

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项与 Ronacaleret Hydrochloride 相关的文献（医药）

2025-04-01·Drug Metabolism and Disposition

Significance of gut breast cancer resistance protein versus organic anion transporting polypeptide 2B1 inhibition on rosuvastatin clinical drug-drug interactions

Article

作者: Lazzaro, Sarah ; Costales, Chester ; Varma, Manthena V S ; Yee, Sook Wah ; West, Mark A ; Morrow, Riley

Organic anion transporting polypeptide (OATP)2B1 facilitates oral absorption of many drugs including celiprolol, fexofenadine, and rosuvastatin. The present study aimed to examine the relevance of gut OATP2B1 and breast cancer resistance protein (BCRP) inhibition in rosuvastatin drug-drug interactions (DDIs). We first characterized OATP2B1-mediated transport of rosuvastatin in transfected cells as a function of extracellular pH 6.0 and 7.4. Rosuvastatin transporter-specific uptake was found to be pH sensitive with 2-fold higher V_max at acidic pH; however, OATP2B1 affinity (K_m = 8-10 μM) was similar at both conditions. We next studied the effect of 26 inhibitor drugs on rosuvastatin OATP2B1-specific transport at 2 pH conditions. Measured IC₅₀s were generally consistent between the 2 pHs (∼88% with 2-fold). For an additional 23 drugs, OATP2B1 IC₅₀ was obtained only at pH 7.4 due to observed limited pH dependency. Inhibition of BCRP-mediated rosuvastatin transport was also acquired at pH 7.4 for 40 compounds using membrane vesicles assay. Finally, the static model for gut interactions (G-value, I₂/IC₅₀) was employed to project in vivo DDI potential. A significant relationship was observed between the BCRP G-value and rosuvastatin area under the curve (AUC) ratio; however, no correlation was apparent with the OATP2B1 G-value. The majority of inhibitors with BCRP G-values >100 perpetrated a "positive" DDI (AUC ratio >1.25). Ronacaleret and elagolix reduced rosuvastatin AUC by 40%-50%, likely due to stronger OATP2B1 inhibition compared with BCRP inhibition. The present study indicates that the "net-effect" of BCRP and OATP2B1 lead to a "positive" DDI, whereas a "negative" DDI (AUC ratio <0.8) is possible for "OATP2B1-alone" inhibitors. SIGNIFICANCE STATEMENT: Gut organic anion transporting polypeptide (OATP)2B1 and breast cancer resistance protein (BCRP) play key roles in rosuvastatin oral absorption and may determine its drug-drug interactions (DDIs). Based on a comprehensive dataset, it was found that rosuvastatin area under the curve ratios correlate significantly with BCRP inhibition, but not with OATP2B1 inhibition. Strong BCRP inhibition, with a G-value >100, translated to "positive" DDIs, whereas "OATP2B1-alone" inhibitors may lead to "negative" DDIs. For example, ronacaleret and elagolix significantly reduced rosuvastatin area under the curve due to strong OATP2B1 inhibition but weak BCRP inhibition.

2020-12-10·The Journal of Physical Chemistry A3区 · 化学

Dispersion-Corrected DFT Methods for Applications in Nuclear Magnetic Resonance Crystallography

3区 · 化学

Article

作者: Holmes, Sean T. ; Schurko, Robert W. ; Vojvodin, Cameron S.

Nuclear electric field gradient (EFG) tensor parameters depend strongly on electronic structures, making their calculation from first principles an excellent metric for the prediction, refinement, and optimization of crystal structures. Here, we use plane-wave density functional theory (DFT) calculations of EFG tensors in organic solids to optimize the Grimme (D2) and Tkatchenko-Scheffler (TS) atomic-pairwise force field dispersion corrections. Refinements using these new force field correction methods result in better representations of true crystal structures, as gauged by calculations of 177 ¹⁴N, ¹⁷O, and ³⁵Cl EFG tensors from 95 materials. The most striking result is the degree by which calculations of ³⁵Cl EFG tensors of chloride ions match with experiment, due to the ability of these new methods to properly locate the positions of hydrogen atoms participating in H···Cl^- hydrogen bonds. These refined structures also feature atomic coordinates that are more similar to those of neutron diffraction structures than those obtained from calculations that do not employ the optimized force fields. Additionally, we assess the quality of these new energy-minimization protocols for the prediction of ¹⁵N magnetic shielding tensors and unit cell volumes, which complement the larger analysis using EFG tensors, since these quantities have different physical origins. It is hoped that these results will be useful in future nuclear magnetic resonance (NMR) crystallographic studies and will be of great interest to a wide variety of researchers, in fields including NMR spectroscopy, computational chemistry, crystallography, pharmaceutical sciences, and crystal engineering.

2020-04-01·British Journal of Pharmacology

Negative allosteric modulators of the human calcium‐sensing receptor bind to overlapping and distinct sites within the 7‐transmembrane domain

Article

作者: DeBono, Aaron ; Gregory, Karen J. ; Leach, Katie ; Josephs, Tracy M. ; Langmead, Christopher J. ; Kufareva, Irina ; Khajehali, Elham ; Keller, Andrew N. ; Capuano, Ben ; Conigrave, Arthur D.

Background and PurposeNegative allosteric modulators (NAMs) that target the calcium‐sensing receptor (CaS receptor) were originally developed for the treatment of osteoporosis by stimulating the release of endogenous parathyroid hormone, but failed in human clinical trials. Several chemically and structurally distinct NAM scaffolds have been described, but it is not known how these different scaffolds interact with the CaS receptor to inhibit receptor signalling in response to agonists.Experimental ApproachIn the present study, we used a mutagenesis approach combined with analytical pharmacology and computational modelling to probe the binding sites of four distinct NAM scaffolds.Key ResultsAlthough all four scaffolds bind to the 7‐transmembrane and/or extracellular or intracellular loops, they occupy distinct regions, as previously shown for positive allosteric modulators of the CaS receptor. Furthermore, different NAM scaffolds mediate negative allosteric modulation via distinct amino acid networks.Conclusion and ImplicationsThese findings aid our understanding of how different NAMs bind to and inhibit the CaS receptor. Elucidation of allosteric binding sites in the CaS receptor has implications for the discovery of novel allosteric modulators.

项与 Ronacaleret Hydrochloride 相关的新闻（医药）

2024-12-31

·漫游药化

如何拯救Heck反应？

第一作者：Qiaogong Su 通讯作者：Qiaogong Su 通讯单位：GlaxoSmithKline DOI：10.1021/acs.oprd.0c00432 引言分享一个工艺研究成果，该文章发表在《OPRD》期刊该研究报道了溶剂中杂质对于Heck反应的影响：在溶剂NMP中过氧化物的存在，会导致Heck反应的失败。因为过氧化物的存在，膦配体从三价被氧化到五价，从而失去促进Heck反应的作用，导致该反应速率急剧下降甚至无法发生 1 简介 Heck反应，即钯催化烯烃的芳基化或烯基化反应。这是一个非常重要的C-C成键反应。该反应最早在二十世纪七十年代被报道，随后被广泛应用于天然产物、药物中间体的合成。对于活性较低的溴代物或氯代物，膦配体可以起到稳定和活化钯催化剂，提高Heck反应效率的作用。 1-甲基-2-吡咯烷酮（NMP）广泛应用在钯催化交叉偶联反应中，同样在Heck反应中大量应用，这主要是因为该溶剂对于有机化合物具有良好的溶解能力，同时有着很高的沸点。 2探索在制备药物Ronacaleret Hydrochloride时，其中涉及一个关键的Heck反应：经过研究，发现最优反应条件为：0.5 mol % of Pd(OAc)2 and 1.5 mol % of P(o-tol)3 ，使用三倍量甲苯为溶剂，同时加入0.75倍量NMP作为共溶剂，以提高原料的溶解性。在该反应条件下，氮气氛围中，通常在95 oC反应2-3小时，大于99.5%的原料1消耗完全。然而，在实验室重复该反应时候，发现实验失败。即使使用氮气将溶剂中的氧尽可能除去，反应仍然较为缓慢。为了获得吨规模的化合物2，必须对该反应进行深入研究，以便解决该问题 3过氧化物研究接下来，进行详细研究：使用HPLC对反应很慢的Heck反应进行检测，结果发现：相对于早期良好的反应，该慢反应中存在较大含量的氧膦化合物进一步分析，发现这些慢反应使用的是存储时间较久的NMP溶剂。随后推测，NMP与氧气反应，会生成过氧化物NMP-5-OOH，该化合物会将底物氧化。在Heck反应中则把容易氧化的三价膦氧化至五价的氧膦，从而导致该反应速率下降。体系中NMP-5-OOH将底物氧化后，转化为NMP-5-OH。接下来，进一步被氧化为N-甲基丁儿酰亚胺（NMS）随后，作者对于NMP进行研究：使用新的NMP溶剂进行Heck反应，结果体系中仅生成4%的氧膦，96%三价膦保持，这个结果与不用NMP溶剂进行Heck反应一样当NMP开封一个月后，检测发现该溶剂中含有0.1 mol%的过氧化物，进行Heck反应时，8%氧膦生成当NMP开封5月后，体系中过氧化物含量进一步增加，到0.46%，此时，再使用该溶剂进行Heck反应，发现体系中全部三价膦均被氧化为五价。这是因为，当使用0.75体积的NMP时候，体系中含有的过氧化物NMP-5-OOH含量达到了1.8 mol%，而反应中膦的用量为1.5 mol%，所以全部都会被氧化至五价。接下来，作者又做了一个加速氧化实验：向NMP中通入空气，可以发现，随着溶剂NMP通空气的时间增加，溶剂中过氧化物逐渐稳步提高 4对反应影响应用接下来，研究不同过氧化物含量对反应的影响：使用新的NMP，没有NMP-5-OOH，结果Heck反应可以在两个小时完成，并且原料1几乎完全转化当使用含有0.46 mol%过氧化物的NMP时，反应两小时，原料1还剩余15%，延长反应至21小时，仍有1%的1未转化作者又做了无配体情况下的对照实验：结果，无过氧化物的NMP，在反应2.5小时后，以93%的收率获得目标化合物2；而存在过氧化物时候，还有9%原料1剩余，并且目标化合物2的收率仅52% 可见溶剂NMP中过氧化物对Heck反应的收率、转化率、反应速率影响巨大评述通过对一个失败的反应，进行深入的研究，发现了解决的办法失败的反应不可怕，深入研究，发现了问题的根本，即可顺利、完好地解决问题

100 项与 Ronacaleret Hydrochloride 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D08991	-	-	DB05255

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
骨质疏松症	临床2期	挪威	GSK Plc	2007-05-14
骨质疏松症	临床2期	俄罗斯	GSK Plc	2007-05-14
骨质疏松症	临床2期	阿根廷	GSK Plc	2007-05-14
骨折	临床2期	-	Shire Pharmaceuticals Services Ltd.	-
造血干细胞移植	临床2期	-	GSK Plc	-
造血干细胞移植	临床2期	-	Shire Pharmaceuticals Services Ltd.	-
造血干细胞移植	临床2期	-	GSK Plc	-
造血干细胞移植	临床2期	-	Shire Pharmaceuticals Services Ltd.	-
绝经期后骨质疏松	临床2期	欧盟	GSK Plc	-
干细胞动员	临床2期	美国	GSK Plc	-

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00471237 (CR9108963, CTgov)	临床2期	骨质疏松症	564	Alendronate+placebo+ronacaleret+calcium+vitamin D	衊鏇齋製積廠築衊襯網(憲鬱獵壓選醖艱夢壓襯) = 鏇繭獵遞願鏇衊窪廠繭齋襯選糧蓋鑰齋餘鹽窪 (窪齋夢築夢觸願築願糧, 醖觸鹽觸艱齋壓繭憲鏇 ~ 憲積齋獵憲鏇鹽觸獵蓋) 更多	-	2017-09-05
ASN2011	N/A	肾脏损伤	-	Ronacaleret 150 mg/kg/day	(願餘觸鹹襯鬱鏇糧獵築) = 顧夢鹹觸蓋醖鑰鑰獵顧築簾醖醖選蓋糧積糧築 (艱蓋願糧淵觸衊網積繭, 0.6) 更多	积极	2011-11-08
				Calcitriol 30 ng/kg/day	(願餘觸鹹襯鬱鏇糧獵築) = 衊膚範窪簾齋鹹築遞範築簾醖醖選蓋糧積糧築 (艱蓋願糧淵觸衊網積繭, 0.5) 更多
NCT00471237 (Pubmed \| J Clin Endocrinol Metab)	临床2期	代谢性骨病	569	Ronacaleret	鏇獵範齋糧壓廠膚壓顧(簾繭鹽範衊窪鹽鑰衊選) = 構願製簾齋鹽壓構製淵壓鬱鏇衊網醖壓繭構齋 (觸網衊壓憲壓齋顧齋憲 )	-	2011-08-01
				Teriparatide	鏇獵範齋糧壓廠膚壓顧(簾繭鹽範衊窪鹽鑰衊選) = 窪鹹範餘糧膚築膚積壓壓鬱鏇衊網醖壓繭構齋 (觸網衊壓憲壓齋顧齋憲 )