The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ 1 R) and the μopioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ 1 R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ 1 R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ 1 R antagonism may be a useful strategy for obtaining potent and safer analgesics.

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ1 receptor (σ1R) ligands are reported. The compounds were prepared using a 4-5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ1R, and the selectivity over the σ2R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ1R potency a minimum lipophilicity was required, while limiting to a defined range of cLogP avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound 13g exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character.

In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log P) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log P values obtained by shake-flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required. In the case of zwitterionic and amphoteric compounds, either for shake-flask and chromatographic methods, the pH has to be accurately selected in order to ensure the compound to be in its neutral form.

correlations indicate holdup time for cations are similar or slightly lower than holdup time for neutral compounds (0.77-0.83 min). The model proposed and the correlations obtained can be very useful for its implementation in retention prediction algorithms for optimization of separation purposes.

Co-crystal of tramadol–celecoxib (CTC) is a novel active pharmaceutical ingredient API–API co-crystal formed by an intrinsic 1:1 molecular ratio of rac-tramadol·HCl (TRM) and celecoxib (CXB) in late-stage development for the treatment of pain. In line with previous intrinsic dissolution rate studies, we report here that the kinetic dissolution profile of CTC in hydroxypropyl methyl cellulose and buffered solutions led to a supersaturation state of CXB and a release significantly faster from CTC than from the free combination, which in turn was quite similar to the release from CXB alone. Inversely, TRM was released much more slowly from CTC than from the free combination and TRM alone. Experimental and predicted solubility–pH curves showed that the thermodynamic solubility of CTC lies in between those of TRM and CXB within the physiologically meaningful pH range. The lattice and solvation contributions to CTC aqueous solubility was studied, showing that the solvation factor is the most important, but it appears to be proportionally lower and more similar to the more soluble component, TRM. These results, together with those obtained in the hygroscopicity studies, show that CTC co-crystal structure provides a clear differential profile versus the free combination or the two APIs alone.

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Predictive software packages to estimate the lipophilicity of molecules have become key tools in the new drug design. Six different well-known computational programs including the classical BioByte-clogP and the GALAS algorithm offered by ACDlabs were evaluated through a set of 103 drugs with different structures and functionalities. To evaluate the predictions accuracy, reliable experimental log P o/w values for the whole testing set were carefully selected. The best estimations are performed by GALAS/logP based on the fragmental method, corrected according to the similarity with compounds included in the software training set.