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Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
Cleghorn et al. (2015) conducted a phenotypic screening of compounds against T. b. brucei followed by a mammalian cell counterscreen (MRC-5 cells) to exclude nonselective compounds. This work led to indoline-2-carboxamide 72 (Figure 26) which showed good activity (EC50 = 27 nM) and selectivity over mammalian cells (> 1600 fold). With compound 72 in hand, SAR studies were realized in terms of core modifications and the effect of stereochemistry on the chiral center. These studies led to the discovery of two new compounds, 73 and 74 (racemic), with lower activity against T. b. brucei (EC50 = 60 and 80 nM, respectively) but with improved metabolic stability and enhanced in vivo exposure. These compounds exhibited excellent pharmacokinetic properties, and resulted in a full cure in a HAT stage 1 mouse model, but unfortunately only a partial cure in stage 2. Structures of potent indoline-2-carboxamides 72–74.
Structure and function of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
It has been reported that pactimibe, a novel acyl coenzyme A/cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases, and its metabolite R-125528 are metabolized by CYP2D6 via ω-1 oxidation (Kotsuma et al. 2008c). The indolin oxidation of pactimibe is mediated by CYP3A4. Both pactimibe and R-125528 are atypical substrates for CYP2D6 because of its acidity. Both compounds are not protonated but are negatively charged at physiological pH. The Km value of R-125528 in CYP2D6-expressing microsomes is 1.74 μM, which is comparable to those of typical basic CYP2D6 substrates (1–10 μM). Pactimibe has a lower affinity than R-125528 to CYP2D6, although the Km value is comparable to that of metoprolol. Interestingly, their sites of metabolism, the ω-1 position of the N-octyl indoline/indole group, are relatively distant from the aromatic moiety. An induced-fit docking of the ligands to a crystal structure of substrate-free CYP2D6 indicated the involvement of an electrostatic interaction between the carboxyl group and Arg221, and hydrophobic interaction between the aromatic moiety and Phe483 (Kotsuma et al. 2008a). With the concomitant treatment of ketoconazole, AUC of pactimibe in healthy subjects increased 1.7-fold and the AUC of R-125528 decreased by 55%. With the concomitant treatment of quinidine, the AUC for pactimibe increased 1.7-fold but the AUC of R-125528 is markedly elevated 5.0-fold (Kotsuma et al. 2008b). As the estimated metabolic fraction of pactimibe by CYP3A4 and CYP2D6 from in vitro studies is 0.40 and 0.33, respectively, AUC increase ratios of pactimibe are estimated to be 1.7 with ketoconazole and 1.5 with quinidine. It can be expected that PMs would have significantly increased concentrations of R-125528 and moderately increased pactimibe levels.
Drug Discovery: From Hits to Clinical Candidates
Published in Divya Vohora, The Third Histamine Receptor, 2008
Sylvain Celanire, Florence Lebon, Holger Stark
From the same group, another class of compound within the aminopropoxyquinoline series has been recently reported [178]. Starting from tetrahydroisoquinoline (THiQ) scaffold 141, identified following medium-throughput screening campaign, and displaying nanomolar antagonism potency (hH3 pKi 8.6), a selected diversity of lipophilic (e.g., ethyl and cyclohexylmethyl) or polar (e.g., thiophenoyl and phenylsulfonyl) residues onto the nitrogen atom were investigated around the THiQ and the tetrahydroquinoline (THQ) analogs (Figure 5.19). The 6- and 7-substituted THiQs (142 and 143, respectively) were generally more potent than their 5- and 8-substituted THQ regioisomers, with a more pronounced subnanomolar affinity for the di-basic one (e.g., 142a, hH3 pKi 9.3; 143a, hH3 pKi 9.3). With the exception of THiQ 143b (hH3 pKi 9.5), the introduction of a phenylsulfonyl group onto all nitrogen-regioisomers led to 10-fold less potent compounds. Further derivatization of the central core was explored, and particularly, the access to the benzoazepane ring system, as exemplified by selected compound 144a ,b, displaying high potency (e.g., 144b, hH3 pKi 9.7; rH3 pKi 8.9) [179]. The introduction of polar groups (acyl, methylsulfonyl) led to monobasic compounds with weaker affinity (~1-log unit decrease) at the rH3R than at the hH3R. Compounds 143a and 144b were further profiled, displaying nanomolar hH3R inverse agonism potency in a GTPγS-binding assay (143a pIC50 9.0; 144b pIC50 8.8) as well as more than 1500-fold selectivity versus the other histamine receptor subtypes. Both compounds had good oral brain penetration as observed in a rat ex vivo binding assay, with an IC50 of 1.1 and 5.3 mg/kg for compounds 143a and 144b, respectively. Moreover, both compounds showed adequate pharmacokinetic properties in rat (>69% oral bioavailability). In a patent application, indoline 145 was also claimed as a potent H3 antagonist (pKi 9.3) [180], demonstrating that the benzo-fused cyclic amine represented an attractive scaffold that both Lilly and GSK have successfully explored. Another distinct chemical class has also been claimed by the same group around the aminoalkyloxazolyl phenyl derivatives, as exemplified by compound 146 with potent H3 antagonism properties (hH3 pKi 7.8).
An updated patent review of VEGFR-2 inhibitors (2017-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Thoraya A. Farghaly, Wedian A. Al-Hasani, Hanan Gaber Abdulwahab
Among the VEGF receptors, VEGFR-2 stands out as the most critical factor in promoting angiogenesis. VEGFR-2 is apparently hyper-activated or over-expressed in many types of solid tumors such as renal carcinoma, colorectal, and lung cancers [7–9]. As a druggable main player in cancer development, VEGFR-2 is well-recognized as the most important target for anti-angiogenesis therapy against cancer. Extensive efforts have been made for the design and development of small molecules VEGFR-2 inhibitors [10–13]. As a consequence, several VEGFR-2 inhibitors have reached the market, resulting in a great therapeutic response and numerous candidate drugs were also clinically tested [10–13]. For example, Sorafenib, a urea derivative, was clinically approved in 2005 for the treatment of metastatic renal cancer, hepatocellular carcinoma, and thyroid cancer. In 2006, the indoline derivative, Sunitinib, reached the clinic for the treatment of renal cell carcinoma, gastrointestinal stromal tumor, and non-small-cell lung carcinoma. Later on, Pazopanib was approved in 2009 as a VEGFR-2 inhibitor for the treatment of renal cell carcinoma and soft tissue sarcomas. Moreover, the quinolone derivatives; Lenvatinib, Vandetanib, Cabozantinib, are clinically used for the treatment of thyroid cancer, melanoma, renal cell carcinoma, kidney cancer, and prostate cancer [10–13].
Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Sara T. Al-Rashood, Ahmed R. Hamed, Ghada S. Hassan, Hamad M. Alkahtani, Abdulrahman A. Almehizia, Amal Alharbi, Mohammad M. Al-Sanea, Wagdy M. Eldehna
Observing the aforementioned results for the anti-proliferative activity MTT assay against HepG2 cells, certain structure activity relationships could be concluded. Firstly, we examined the effect of C-5 substitution of the indoline moiety. 5-Br substituted spirooxindoles 6i–6l displayed more enhanced anti-proliferative activity (IC50 = 6.3, 9.9, 13.2 and 12.7 µM, respectively) than their corresponding unsubstituted spirooxindoles 6a–6d (IC50 = 6.9, 21.0, 19.1 and 49.1 µM, respectively), 5-Cl substituted spirooxindoles 6e–6h (IC50 = 8.4, 32.7, >50.0 and 19.9 µM, respectively), and 5-OCH3 substituted spirooxindoles 6 m–6p (IC50 = 30.6, >50.0, >50.0 and >50.0 µM, respectively), which highlighted that C-5 substitution of the indoline moiety with the large lipophilic Br group is more advantageous for the growth inhibitory activity against HepG2 cells than substitution with smaller lipophilic (as Cl and OCH3) groups and unsubstitution.
One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Wagdy M. Eldehna, Dina H. EL-Naggar, Ahmed R. Hamed, Hany S. Ibrahim, Hazem A. Ghabbour, Hatem A. Abdel-Aziz
Based on the aforementioned results of the biological anti-proliferative activity assay, important structure activity relationships could be deduced. Firstly, we investigated the impact of the C-5 substitution of the indoline moiety. The abolished activity of 5-methoxyindoline derivatives 6n–p along with the decreased IC50 value of 6m, with incorporated unsubstituted phenyl group, (17.50 µM) than that of its corresponding members 6a, 6e and 6i, with unsubstituted, 5-chloro substituted and 5-bromo substituted indoline moiety, (6.70, 6.40 and 6.70 µM, respectively) indicated that unsubstitution or C-5 substitution of the indoline moiety with electron withdrawing groups (EWGs), as 5-Cl or 5-Br, is more beneficial than incorporation of electron-donating substituents, as 5-OCH3, to the growth inhibitory activity against MDA-MB-231 cells.