Barriers to conducting cancer trials in Canada: an analysis of key informant interviews.

Background: In Canada, there is growing evidence that oncology clinical trials units (ctus) and programs face serious financial challenges. Investment in cancer research in Canada has declined almost 20% in the 5 years since its peak in 2011, and the costs of conducting leading-edge trials are rising. Clinical trials units must therefore be strategic about which studies they open. We interviewed Canadian health care professionals responsible for running cancer trials programs to identify the barriers to sustainability that they face. Methods: One-on-one telephone interviews were conducted with clinicians and clinical research professionals at oncology ctus in Canada. We asked for their perspectives about the barriers to conducting trials at their institutions, in their provinces, and nationwide. Interviews were digitally recorded, transcribed, anonymized, and coded in the NVivo software application (version 11: QSR International, Melbourne, Australia). The initial coding structure was informed by the interview script, with new concepts drawn out and coded during analysis, using a constant comparative approach. Results: Between June 2017 and November 2018, 25 interviews were conducted. Key barriers that participants identified were■ insufficient stable funding to support trials infrastructure and retain staff;■ the need to adopt strict cost-recovery policies, leading to fewer academic trials in portfolios; and■ an overreliance on industry to fund clinical research in Canada. Conclusions: Funding uncertainties have led ctus to increasingly rely on industry sponsorship and more stringent feasibility thresholds to remain solvent. Retaining skilled trials staff can create efficiencies in opening and running studies, with spillover effects of more trials being open to patients. More academic studies are needed to curb industry's influence.

Pharmacological characterisation of the enantiomers of BM-5, a muscarinic partial agonist with opposed enantioselectivity between affinity and efficacy.

The interaction of (R) and (S) enantiomers of the chiral oxotremorine analogue BM-5 with muscarinic acetylcholine receptors was studied in vitro using radioligand binding and isolated tissue preparations. The in vivo effects of (R)-BM-5 were also studied in anaesthetised cat. No receptor or tissue selectivity was found for either enantiomer in radioligand binding studies in cells expressing human muscarinic receptors (M1-M5) or in guinea pig tissues. The affinity of (R)-BM-5 was about 40 times, or 15-60 times higher than that of (S)-BM-5 in recombinant cells or in guinea pig tissues, respectively. Both enantiomers induced contraction of the guinea pig isolated urinary bladder and ileum. (R)-BM-5 was more potent than (S)-BM-5 in bladder (EC50 590 and 3500 nM, respectively) and in ileum (EC50 39 and 2600 nM, respectively). The maximal agonist effect was lower for (R)-BM-5 than for (S)-BM-5 in bladder (2.7% and 6.6%, respectively) and in ileum (32% and 48%, respectively). Contractions were completely inhibited by atropine (1 microM). In vivo, (R)-BM-5 induced bladder contraction and salivation after intravenous administration in the anaesthetised cat (ED50 4.1 and 6.2 microg kg(-1), respectively). In conclusion, (R)- and (S)-BM-5 act as partial muscarinic agonists in the isolated bladder and ileum. (R)-BM-5 was the more potent enantiomer but had a lower maximal agonist effect giving an opposed enantioselectivity for affinity and efficacy. (R)-BM-5 showed agonist activity in vivo, confirming in vitro findings. From affinity and efficacy data it can be concluded that the effects of racemic BM-5 are mediated by the (R)-enantiomer.

Stereoisomers of 3-(2,3-dihydrobenzofuran-2-yl)quinuclidine: preparation and muscarinic receptor affinities.

The four stereoisomers of the antimuscarinic 3-(2,3-dihydrobenzofuran-2-yl)quinuclidine have been prepared by a method involving chromatographic separation of the racemic diastereoisomers as borane complexes. The relative and absolute configurations of the stereoisomers were determined by X-ray crystallographic methods. The crystal structure of (2'R,3R)-3-(2,3-dihydrobenzofuran-2-yl)quinuclidine.HCl.H2O contains two independent molecules with different conformations of both the quinuclidine moiety and the dihydrofuran ring.

Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists.

Tolterodine [(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine ] is a new potent and competitive muscarinic receptor antagonist developed for the treatment of urinary urge incontinence and other symptoms of overactive bladder. In vivo, tolterodine exhibits functional selectivity for the urinary bladder over salivary glands, a profile that cannot be explained in terms of selectivity for a single muscarinic receptor subtype. The aim of this study was to compare the in vitro and in vivo antimuscarinic profiles of tolterodine with those of muscarinic receptor antagonists with distinct receptor subtype-selectivity profiles: darifenacin [(S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]-2,2-d iphenylacetamide; selective for muscarinic M3 receptors]; UH-AH 37 (6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-dibenzo-[b ,e][1,4]diazepine-11-one; low affinity for muscarinic M2 receptors); and AQ-RA 741 (11-([4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl)-5,11-dihydro-6H-py rido[2,3-b][1,4]benzodiazepine-6-one; high affinity for muscarinic M2 receptors). The in vitro profiles of these compounds were in agreement with previous reports; darifenacin and UH-AH 37 demonstrated selectivity for muscarinic M3/m3 over M2/m2 receptors, while the converse was observed for AQ-RA 741. In vivo, AQ-RA 741 was more potent (1.4-2.7-fold) in inhibiting urinary bladder contraction than salivation in the anaesthetised cat (i.e., a profile similar to that of tolterodine [2.5-3.3-fold]), while darifenacin and UH-AH 37 showed the reverse selectivity profile (0.6-0.8 and 0.4-0.5-fold, respectively). The results confirm that it is possible to separate the antimuscarinic effects on urinary bladder and salivary glands in vivo. The data on UH-AH 37 and darifenacin support the view that a selectivity for muscarinic M3/m3 over M2/m2 receptors may result in a more pronounced effect on salivation than on bladder contraction. The data on AQ-RA 741 may indicate that muscarinic M2/m2 receptors may have a role in bladder contraction.

Antimuscarinic 3-(2-furanyl)quinuclidin-2-ene derivatives: synthesis and structure-activity relationships.

A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (Ki = 300 nM), it is much higher for the 5-methyl (48; Ki = 12 nM), 5-ethyl (52; Ki = 7.4 nM), 5-bromo (33; Ki = 6.4 nM), and 3-phenyl (49; Ki = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (Ki = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta- and para-substituted analogues of 49 was synthesized and tested. The m-hydroxy derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.

3-(2-Benzofuranyl)quinuclidin-2-ene derivatives: novel muscarinic antagonists.

A series of 26 derivatives of the novel muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for muscarinic and antimuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic-potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure-activity relationship models were developed for this series of substituted benzofuranyl derivatives.

3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships.

A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.

Quinuclidin-2-ene-based muscarinic antagonists.

A series of achiral 3-heteroaryl substituted quinuclidin-2-ene derivatives and related compounds have been synthesized by facile methods. The compounds were evaluated for muscarinic and antimuscarinic properties in receptor binding studies using (-)-[3H]-QNB as the radioligand and in a functional assay using isolated guinea pig urinary bladder. 3-(2-Benzofuranyl)-quinuclidin-2-ene (15) displayed the highest M1-receptor affinity in the present series (Ki = 9.6 nM).

Analogues of the muscarinic agent 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane]: synthesis and pharmacology.

A number of tetrahydrofuran analogues of 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane] (1) have been prepared with the aim to obtain information about the relative importance of each of the oxygens in 1 for efficacy and for selectivity. In addition, the dimethyl and desmethyl analogues of 1 were prepared. The new compounds were compared to cis- and trans-1 with regard to their ability to displace (-)-[3H]-3-quinuclidinyl benzilate ((-)-[3H]QNB) from muscarinic receptors in cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs. Functional studies were made on isolated guinea pig bladder and ileum. The new compounds exhibited both lower affinity and efficacy than cis-1. A conformational study was performed, and the effects of steric and electronic factors on the biological activity of the compounds are discussed.