1,3-Disubstituted 4-aminopiperidines as useful tools in the optimization of the 2-aminobenzo[a]quinolizine dipeptidyl peptidase IV inhibitors

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

“…The lipophilic S 1 pocket is considered a crucial molecular anchor point for DPP‐IV inhibitors, and the residues that constitute this pocket are conserved among the peptidases DPP‐IV, DPP8, and DPP9 . Figure and Supporting Information Figure describe two different ways for increasing the bioactivity of DPP‐IV inhibitors through hydrophobic interactions with the S 1 pocket: (a) replacing a but‐2‐yn‐1‐yl substituent by a prenyl group (with associated improvements in bioactivity in a 1.7 to 125‐fold range; see Figure A and Supporting Information Figure A–G); and (b) replacing a monobutyl substituent by either an m‐tolyl or a phenyl group (with respectively 113‐ and 2.6‐fold associated improvements in bioactivity; see Figure B and Supporting Information Figure H) . In all the comparisons in Figure and Supporting Information Figure we observe a tendency in which those compounds presenting a better occupancy of the S 1 pocket achieved higher bioactivities.…”

Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation

“…A C C E P T E D ACCEPTED MANUSCRIPT 19 cases of functional group cooperativity have been reported within the context of SAR studies [38][39][40][41][42]. Functional group cooperativity can be described as the dependency of the functional group contributions to the binding affinity on the structural features of the rest of the ligand molecule.…”

Libraries of 2,3,4,6,7,11b-Hexahydro-1H-pyrido[2,1-a]isoquinolin-2-amine Derivatives via a Multicomponent Assembly Process/1,3-Dipolar Cycloaddition Strategy

“…13 Moreover, compounds containing the 2,3,4,6,7,11 b -hexahydro-1 H -pyrido[2,1- a ]isoquinoline-2-amine scaffold ( 1 ) are documented as α 2 -adrenoceptor antagonists ( 2–4 ), 14 opioid receptor antagonists ( 5 ), 15 and dipeptidyl peptidase IV (DPP-IV) inhibitors ( 6 ) 16 (Figure 1). We have recently reported a method for the rapid and efficient assembly of the scaffold comprising 1 via an MCAP/1,3-dipolar cycloaddition strategy.…”