Designing Drugs to Avoid Toxicity

Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354

“…Due to the presence of the aryl nitro group found within ML354, which can be associated with toxicological challenges, 18,19 and its recently measured in vitro DMPK profile (see Fig. 3, high plasma protein binding and metabolic turnover, and poor cytochrome P450 inhibition profile), ML354 remains limited to in vitro experiments using isolated platelets.…”

Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors

“…TYK2 inhibitory activity and JAK2 selectivity of a compound bearing propan-2-ol (20) slightly decreased compared to those of the morpholine derivative (17). The above results demonstrated that further improvement in TYK2 inhibitory activity was achieved by the optimization of the 5-and 7-positions of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one, through (1) occupying the JAK pocket efficiently with a chiral alkyl group and (2) by additional interaction with the amino acid residues in the solvent exposed (14)(15)(16)(17)(18)(19) [7.6] 17 (13-22) [8.1] 3.3 (3.0-3.6) [1.6] 190 (75-480) a The enzyme inhibition assay using JAK1-3, or TYK2 enzymes. b Inhibitory activity of IL-23-induced luciferase gene expression in Jurkat cells.…”

“…Reagents and conditions: (a) 2,2,6-trimethyl-4H-1,3-dioxin-4-one, NaOAc, THF, reflux, 74% for 22c; (b) diketene, MeOH, 0 °C, 96% for 22d; (c) K 2 CO 3 , DMF/DMA, DMF, rt, 69-84% for 23a-b, d; (d) DMF/DMA, DMF, rt, 95% for 23c; (e) POCl 3 , DMF, 0 °C→100-125 °C, 59-64% for 24a-c; (f) (chloromethylene)dimethylammonium chloride, DMF 100 °C, 57% for 24d, (g) hydroxylamine hydrochloride, NaOAc, MeOH-H 2 O, 75 °C, 77-92% for 25a, 25c; (h) hydroxylamine hydrochloride, conc HCl, 2-propanol, 100 °C, 68-95% for 25b, 25d; (i) POCl 3 , CH 3 CN, 90 °C, 53-100% for 26a-c; (j) SOCl 2 , CH 3 CN, rt, 68% for 26d; (k) NBS, DMF, 50-60 °C, 81-98%; (l) PhB(OH) 2 , Pd(PPh 3 ) 4 , 2 M Na 2 CO 3 aq., DME, 90 °C, 64%; (m) hydrazine monohydrate, EtOH, 70 °C, 27%; (n) hydrazine monohydrate, EtOH, 70-90 °C, 82%-94%; (o) chiral HPLC, CHIRALPAK AD, hexane/EtOH, 44%; (p) KOAc, PdCl 2 (dppf) (or Pd(PPh 3 ) 4 ), bis(pinacolato)diboron, DMF (or DMA), 110-120 °C, then R 2 -Br (or R 2 -I, or R 2 -OTf), Pd(PPh 3 ) 4 , 2 M Na 2 CO 3 aq., 120 °C, 8-41% for 5, 6, 13, 15, 17, 19, 20, 30; (q) 1-methyl-3-(4,4,5,5-tetramethy-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, Pd(PPh 3 ) 4 , 2 M Na 2 CO 3 aq., DMF,120 °C,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]9,16;(r) In order to acquire SAR of 5-position efficiently, an alternative synthetic route was developed (Scheme 2). Pyridone 31 was reacted with alkyl halides, followed by the separation of N-alkylated pyridones from the mixture of N-and O-alkylated products by chromatography to give 32a-c.…”

“…As a result, the compound with an added (morpholin-4-yl)pyridin-2-yl group (13) showed potent TYK2 inhibitory activity (IC 50 = 1.5 nM).Thus the racemic mixtures were separated (14,15). TYK2 inhibitory activity of the (S)-form (14) with subnanomolar IC 50 values was 10-fold more potent than that of the (R)-form (15). Next the effect of introducing substitution at the 5'-position of the 1-methyl-3-pyrazolyl moiety (e.g., [16][17][18][19][20], which were expected to interact with Leu903 or Asp988, was investigated (Figure 3).…”

Development of 1H-Pyrazolo[3,4-b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators

“…While biotransformation studies failed to demonstrate involvement of the acetylene moiety, this functionality has been repeatedly linked with CYP-mediated bioactivation in vivo. 15 In an effort to discover a new, structurally divergent chemotype, we performed a functional high-throughput screen (HTS) of more than 1.1 million compounds in the presence of an EC 10 of glutamate. This effort identified 1H-pyrazolo [3,4-b]pyridine 2 (Figure 1), which represented a novel mGluR5 chemotype with promising submicromolar PAM activity.…”