Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design

Abstract

A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, A12, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure−activity relationship of compound A12, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.

Scalable Synthesis and Cancer Cell Cytotoxicity of Rooperol and Analogues

“…Mp = 34.0-36.0 Methyl (E)-3-(3,5-bis((tert-butyldimethylsilyl)oxy)phenyl)acrylate (4C) [24]: Prepared from aldehyde 8C following the general procedure described for 4A, which afforded 4C as a colorless oil, (3.93 g, 95% yield). IR (ATR, neat) cm −1 2951, 2928, 2857, 1716, 1638, 1578, 1437, 1281, 1154, 1002, 828, 778; 1 H NMR (500 MHz, CDCl 3 ): δ 7.55 (d, 1H, J = 15.9 Hz), 6.62 (dd, 2H, J = 2.2, 0.4 Hz), 6.36 (t, 1H, J = 2.2 Hz), 6.34 (d, 1H, J = 15.9 Hz), 3.80 (s, 3H), 0.98 (s, 18H), 0.20 (s, 12H); 13 Methyl (E)-3-(3,4-difluorophenyl)acrylate (4D) [25]: Prepared from 3,4-difluorobenzaldehyde following the general procedure described for 4A, which afforded 4D as a white solid (3.17 g, 91%). Mp = 76.9-77.9 Methyl (E)-3-(benzo[d][1,3]dioxol-5-yl)acrylate (4E) [26]: Prepared from piperonal following the general procedure described for 4A, which afforded 4E as a white solid (5.4 g, 96%).…”

“…Methyl ( E ) -3- ( 3,4-difluorophenyl ) acrylate ( 4D ) [ 25 ]: Prepared from 3,4-difluorobenzaldehyde following the general procedure described for 4A , which afforded 4D as a white solid (3.17 g, 91%). Mp = 76.9–77.9 °C; IR (ATR, neat): cm −1 3057, 2957, 2920, 1704, 1640, 1514, 1494, 1435, 1330, 1270, 1250, 1220, 1189, 1175, 1144, 1111, 987, 870, 814, 790; 1 H NMR (400 MHz, CDCl 3 ): δ 7.57 (d, 1H, J = 16.0 Hz), 7.32 (ddd, 1H, J = 11.0, 7.6, 2.1 Hz), 7.25–7.21 (m, 1H), 7.20–7.12 (m, 1H), 6.33 (dd, 1H, J = 16.0, 0.3 Hz), 3.79 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 166.8, 151.5 (dd, J = 253, 13 Hz), 153.4 (dd, J = 249, 13 Hz), 142.4, 131.6 (dd, J = 5, 5 Hz), 124.7 (dd, J = 6, 3 Hz), 118.9 (d, J = 2 Hz), 117.8 (d, J = 17 Hz), 116.3 (d, J = 17 Hz), 51.7; 19 F{ 1 H} NMR (376 MHz, CDCl 3 ): δ −134.2 (d, J = 21 Hz), −136.6 (d, J = 21 Hz); MS (APCI, pos) m/z (%): 199(5) [M + H] + .…”

Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity

“…However, we found a critical hydrogen-bond interaction between Glu278 and the nitrogen on the piperidine ring was missing in the complex (Figures 3A and S1B) compared to that in the compound 1− Akt1 complex previously reported. 16 The distance between Glu278 and the nitrogen was too long to form a hydrogen bond during the whole dynamics simulation (Figure 3B). After investigating the binding pose of compound 2, we assumed that hydrogen-bond interaction might be formed through deflecting the piperidine by a certain angle.…”

Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

“…Exemplified inhibitors for this pathway that had been developed and entered clinical trials include: A number of AKT inhibitors acting on two distinct binding sites: ATP-binding site and allosteric pocket of the autoinhibited isoform as shown in Figure 2 18–24 , such as Ipatasertib [GDC0068] I 18 which is a highly selective ATP-competitive pan-Akt inhibitor in phase-III clinical trials to evaluate its effectiveness in triple-negative breast cancer [TNBC] and Capivasertib [AZD5363] II 19 , 20 which is also in phase-III trial to further evaluate its efficacy and safety in combination with paclitaxel in first-line treatment of patients with metastatic TNBC. Likewise, the allosteric pan-AKT inhibitor MK-2206 V 23 demonstrated activity in treating patients with relapsed acute myeloid leukaemia (AML) in phase-II clinical studies.…”