Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events

Abstract Background In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point. Patients and methods Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form. Results Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66–0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65–0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE. Conclusion In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE

Synthesis of new Delta(2)-isoxazoline derivatives and their pharmacological characterization as beta-adrenergic receptor antagonists

A series of Delta(2)-isoxazoline derivatives structurally related to Broxaterol 1 and Falintolol 3 has been prepared and evaluated for their binding affinity to beta(1)- and beta(2)-adrenergic receptors. Among the tested compounds only the 3-isopropenyl anti derivative 4d is as active as the reference compounds. An electron-releasing group, probably operating through a pi-pi interaction, in the 3-position of the isoxazoline nucleus greatly enhances the affinity of the compounds. Conversely, the closest analogs of Broxaterol (3-bromo Delta(2)-isoxazolines 4a and 5a) are at least one order of magnitude less active than the model compound 1. Throughout the series of derivatives the anti stereoisomers are invariably more active than their syn counterparts. (C) 1998 Elsevier Science Ltd. All rights reserved

A novel class of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as A3 adenosine receptor antagonists

Adenosine is an endogenous nucleoside distributed in several mammalian organisms’ tissues. It modulates different important physiological functions. Adenosine cannot be identified as a neurotransmitter because there is no clear evidence that it is stored in or released by specific purinergic nerves, so adenosine is usually considered a neuromodulator. It is well known that adenosine interacts with G-protein-coupled receptors that were classified in four receptors subtypes: A1, A2A, A2B, and A3 adenosine receptors (AR). A2A and A2B ARs stimulate adenylyl cyclase; instead, A1 and A3 ARs inhibit adenylyl cyclase. Moreover A1, A2B and A3 ARs stimulate also phospholypase C. Adenosine receptor antagonists have several potential therapeutic applications. In particular, A1 antagonists are diuretic. Through adenosine antagonist action towards A2A AR, we have a lot of CNS effects, such as neuroprotection, sleep disorder regulation and neurodegenerative disease treatment (Parkinson’s and Huntington’s diseases). A2B AR antagonists could be used in asthma and also as hypoglycemic. A3 antagonism is useful in glaucoma; moreover, due to the fact that A3 AR is widely expressed in some cancer cells, A3 AR antagonists could be used for tumoral diagnosis [1]. It was demonstrated by several studies that pyrazolo-triazolo-pyrimidine (PTP) core is a good template to obtain potent and selective adenosine receptor antagonists [2]. Our attention is focused on A3 ARs because up to now, phenylureidic and phenylacetamidic substitutions in position 5 are the only discovered A3 PTP antagonists where a carbonyl moiety is always present. So we synthesized a novel class of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines bearing an N8-methyl group and different amine moieties in position 5. This kind of derivatives could demonstrate that carbonyl moiety is not essential to have affinity towards A3 ARs

A facile and novel synthesis of N2-, C6-substituted pyrazolo[3,4- d ]pyrimidine-4 carboxylate derivatives as adenosine receptor antagonists

An efficient synthetic procedure was adopted to synthesize a series of new molecules containing the pyrazolo[3,4-d]pyrimidine (PP) scaffold, which have been evaluated as promising human adenosine receptor (AR) antagonists. The effect of substitutions at the N2, C4 and C6 positions of PPs on the affinity and selectivity towards the adenosine receptors were explored. Most of the pyrazolo[3,4-d]pyrimidine-4-carboxylates displayed from moderate to good affinity at the human A3AR (hA3AR), as indicated by the low micromolar range of Ki values (Ki hA3AR \ubc 0.7e34 mM). In particular, compounds 60 and 62 displayed good affinity at the hA3AR (60, Ki hA3AR \ubc 2.2 mM and 62, Ki A3AR \ubc 2.9 mM) and selectivity towards the other AR subtypes (60, >46-fold selective and 62, >34-fold selective, respectively). In view of these results, these novel PP analogues were docked both in the crystallographic structure of the hA2AAR and in a homology model of the hA3AR in order to support the structure activity relationship (SAR) analysis. These preliminary results demonstrated that pyrazolo[3,4-d]pyrimidine can be considered a promising scaffold to obtain new molecules with potent hA3AR antagonist activity

A facile and novel synthesis of N2-, C6-substituted pyrazolo[3,4- d ]pyrimidine-4 carboxylate derivatives as adenosine receptor antagonists

10.1016/j.ejmech.2015.01.046European Journal of Medicinal Chemistry92784-79

Synthesis of enantiopure Delta(2)-isoxazoline derivatives and evaluation of their affinity and efficacy profiles at human beta-adrenergic receptor subtypes

The new enantiomerically pure 3-substituted-Delta(2)-isoxazolin-5-yl-ethanolamines (+)-6a/(-)-6b, (-)-6a/(+)-6b, and (+)-7a/ (-)-7b, prepared via a 1,3-dipolar cycloaddition-based approach, were tested for their affinity at human beta(1)-, beta(2)-, and beta(3)-adrenergic receptor (beta-AR) subtypes stably expressed in CHO cells. The corresponding 3-isopropenyl derivatives (+)-5a/(-)-5b, (-)-5a/(+)-5b, and some isoxazole analogs were also tested. The binding affinities at the beta-ARs of the isoxazolinyl amino alcohols were significantly lower than those of the corresponding isoxazole derivatives. A stereochemical effect was observed, since the process of molecular recognition is predominantly controlled by the (S)-configuration of the stereogenic center located at the 5 position of the heterocycle rather than by that of the stereocenter carrying the secondary alcohol group. On the contrary, the stereochemical features marginally affected the efficacy response; as a matter of fact, functional tests carried out on Delta(2)-isoxazoline derivatives provided with a detectable binding affinity showed the overall profile of neutral antagonists at all three beta-AR subtype

Novel chiral isoxazole derivatives: synthesis and pharmacological characterization at human b-adrenergic receptor subtypes

Isoxazole derivative (\ub1)-4 and the three pairs of stereoisomeric 3-bromo-isoxazolyl amino alcohols (S, R)-(-)-7a/(R, R)-(+)-7b, (S, R)-(-)-8a/(R, R)-(+)-8b, and (S, R)-(-)-9a/(R, R)-(+)-9b were synthesized and assayed for their affinity and efficacy at human \u3b21-, \u3b22-, and \u3b23-adrenergic receptors (\u3b2-ARs) in membranes from Chinese hamster ovary (CHO) cells stably transfected with the respective receptor subtype. Whereas derivative (\ub1)-4 did not bind at all three \u3b2-ARs, stereoisomers (S, R)-7a-(S, R)-9a behaved as high-affinity ligands at \u3b21- and, particularly, at \u3b22-ARs (Ki 2.82-66.7 nM). The Ki values of isomers (R, R)-7b-(R, R)-9b at \u3b21- and \u3b22-subtypes were about 30-100 times higher than those of their (S, R)-7a-9a counterparts, indicating a sizable stereochemical effect. The affinity at \u3b23-ARs was negligible for all the investigated compounds. When submitted to a functional assay, the three stereoisomeric pairs showed a comparable pattern of efficacy at all three \u3b2-AR subtypes. The highest value of efficacy (75-90%) was observed at \u3b22-ARs, whereas all compounds behaved as partial agonists (30-60%) at the \u3b23-subtype. The lowest degree of efficacy (15-35%) was found at \u3b21-ARs. The affinity/efficacy profile of the derivatives under study has been compared with that of the two model compounds, Broxaterol [(\ub1)-1] and BRL 37344 [(\ub1)-6]

Synthesis, biological studies and molecular modeling investigation of 1,3-dimethyl-2,4-dioxo-6-methyl-8-(substituted) 1,2,3,4-tetrahydro [1,2,4]-triazolo [3,4-f]-purines as potential adenosine receptor antagonists

A new series of potential adenosine receptor antagonists with a [1,2,4]-triazolo-[3,4-f]-purine structure have been synthesized, and their affinities at the four adenosine receptor subtypes (A1, A2A, A2B and A3) have been evaluated. The design was based on the demonstrated approach to novel A3 adenosine receptor antagonists of adding a third ring to the xanthine structure. Unfortunately, all the synthesized compds. were completely inactive at all four adenosine receptor subtypes independently of their substitutions. Preliminary mol. modeling investigation has demonstrated that only a low degree of steric and electrostatic complementarity has been obsd. for all the new synthesized triazolo-purines with respect to other structurally related A3 receptor antagonists. This anal. yielded valuable information about structure-activity relationships and further design of potential adenosine receptor antagonist