Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part I: Exploration of 5–6 fused rings as alternative S1 moieties

Abstract

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.

Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents

“…1 H NMR data of compounds 6a–c matched those reported previously in the literature. 52 , 53 A mixture of the 5-bromo and 7-bromo isomers 6g,h were obtained in 1 : 1 ratio from 3-bromoaniline as a starting material and they were separated via recrystallization from dichloromethane (DCM).…”

OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules

“…34,36,37 Consistent with the reported assay conditions, we replaced this water with a sodium ion. 35,37 We also refined ligand starting geometries using a similar strategy to that discussed in ref 39. When there was ambiguity about the pose, such as for symmetric R-groups with meta or ortho substituents that could flip 180 deg, we used FEP+ to assess and select the pose with the lowest free energy.…”

Lead optimization mapper: automating free energy calculations for lead optimization

“…Our main focus here is on a set of 50 Factor Xa (FXa) inhibitors taken from various literature sources[32, 66, 65, 52, 67], and the LOMAP plan for the full set is shown in Figure 2 (with structures for a smaller subset in Figure 3). We also tested a set of potential trypsin inhibitors (a fragment library which was screened for binding to trypsin[42], as well as a substantial number of known trypsin inhibitors), the SAMPL3 [41] set of small molecules, and our set of 504 fragment-like molecules[37, 35].…”