Potent, low molecular weight renin inhibitors containing a C-terminal heterocycle: hydrogen bonding at the active site

Abstract

A series of low-nanomolar renin inhibitors containing novel C-terminal heterocycles has been designed by formally cyclizing the C-terminus of a glycol-based inhibitor to the second hydroxyl. Molecular modeling suggests that the heterocyclic oxygen hydrogen bonds as an acceptor to the flap region of renin and that the second hydroxyl in the glycol-based inhibitors behaves similarly.

Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides

“…C-Terminal Oxazolidinone Renin Inhibitors Containing Heterocycle-Substituted Alanine Residues at the P2 Histidine Site 0 Mean ± SEM, = 3, determined by a renin inhibition assay. 6 Human plasma renin, pH 7. 4.c Octanol/water, pH 7.4. d mg/mL, pH 7.4. e See ref 25.…”

“…After stirring 2 h at -23 °C and 15 h at ambient temperature, the mixture was poured into saturated NaHC03 solution and was extracted into ethyl acetate which was washed with water and brine, and then was dried and evaporated. Chromatography of the residue with 1.5-7 % methanol in chloroform afforded 1.31 g (64%) of a white solid: mp 175-180 "C; TLC (I) Rf = 0.54; NMR (CDCI3) 7.52 (d, 1 H), 6.98 (br d, 1 H), 6.22 (d, 1 ), 5.60 Journal of Medicinal Chemistry, 1993, Vol. 36, No.…”

“…After 3 min amine 2 (341 mg, 1.40 mmol) was added, and the mixture was stirred at -10 °C for 10 min and at ambient temperature for 2 h. The solvent was evaporated, and the residue was taken up in ethyl acetate which was washed with 0.5 M H3P04, saturated NaHC03, and brine, and then was dried and evaporated. Chromatography of the residue with 30 % ethyl acetate in hexane afforded 702 mg (100%) of a foam: TLC (IV) Rf = 0.55; NMR (CDClg) 5 7.22 (dd, 1H), 6.97 (dd, 1H), 6.90 (dd, 1H), 6.00 (br d, 1H), 4.98 (br, 1 ), 4.40-4.25 (m, 3 H), 4.12-4.03 (m, 1 ), 3.25-3.06 (m, 4 ), 1.96-1.82 (m, 1 ), 1.80-0.75 (envelope, 15 ), 1.43 (s, 9 ), 0.95 (d, 3 ), 0.90 (d, 3 H); MS m/e ( + H)+ 497.…”

Influence of Catalyst Structure and Reaction Conditions on anti‐ versus syn‐Aminopalladation Pathways in Pd‐Catalyzed Alkene Carboamination Reactions of N‐Allylsulfamides

“…Cyclic sulfamides are an important class of heterocycle that have attracted attention in medicinal‐chemistry applications as these functional groups can serve as isosteres for cyclic ureas and are also known to form attractive electrostatic interactions with proteins and enzymes 1. Biologically active compounds that bear these units have been examined as protease inhibitors,2 human leukocyte elastase (HLE) inhibitors,3 renin inhibitors,4 and norovirus inhibitors 5. In addition, the SO 2 unit can be cleaved from these compounds to afford synthetically useful 1,2‐diamines 6.…”

“…J = 13.7 Hz, 1 H), 4.13 (d, J = 13.7 Hz, 1 H),3.51 (ddt, J = 5.5, 6.8, 9.4 Hz, 1 H),3.09 (dd, J = 6.9, 9 4. Hz, 1 H), 2.98 (dd, J = 5.2, 13.6 Hz, 1 H), 2.87 (dd, J = 5.8, 9.4 Hz, 1 H), 2.69 (dd, J = 9.6, 13.6 Hz, 1 H), 1.99 ppm (s, 3 H); 13 C NMR (126 MHz, CDCl 3 ): d = 136.3, 135.4, 135.0, 134.4, 130.6, 130.1, 128.9, 128.7, 128.7, 128.7, 128.2, 128.1, 127.1, 126.1, 55.7, 50.7, 50.6, 49.6, 36.8, 19.1 ppm; IR (film): ñ = 1283, 1164 cm À1 ; MS (ESI): m/z calcd for C 24 H 26 N 2 O 2 S: 407.1788 [M + H] + ; found: 407.1790.…”