Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
Drug Design , Indoles/chemical synthesis , Neuralgia/drug therapy , Oxadiazoles/chemical synthesis , Receptor, Cannabinoid, CB1/agonists , Animals , Brain/blood supply , Brain/metabolism , Caco-2 Cells , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Mice , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Rats
Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.
Cathepsins/antagonists & inhibitors , Nitrogen/chemistry , Protease Inhibitors/chemistry , Pyridines/chemistry , Animals , Cathepsins/metabolism , Mice , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Rats, Sprague-Dawley
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
Aniline Compounds/chemical synthesis , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Amides/chemical synthesis , Amides/pharmacology , Aniline Compounds/pharmacology , Animals , Cysteine Proteinase Inhibitors/pharmacology , Fluorine , Humans , Ketones , Structure-Activity Relationship
