ABSTRACT
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
Subject(s)
Cathepsins/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Administration, Oral , Animals , Brain/drug effects , Cathepsin L , Combinatorial Chemistry Techniques , Cysteine Endopeptidases , Humans , Male , Molecular Structure , Multiple Sclerosis/drug therapy , Pain/drug therapy , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.
Subject(s)
Cathepsins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Cysteine Proteinase Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Peptides/chemistry , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Animals , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Male , Molecular Conformation , Nitriles/pharmacology , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.
Subject(s)
Analgesics/chemical synthesis , Brain/metabolism , Hyperalgesia/drug therapy , Naphthalenes/chemical synthesis , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Administration, Oral , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Biological Availability , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Humans , In Vitro Techniques , Microsomes, Liver/metabolism , Naphthalenes/pharmacokinetics , Naphthalenes/pharmacology , Radioligand Assay , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.