ABSTRACT
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 µM). Compound 6s demonstrated free-plasma exposures above the IC50 (â¼50×) with a brain-to-plasma ratio of â¼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
Subject(s)
Cognition/drug effects , Cyclopropanes/chemical synthesis , Histamine H3 Antagonists/chemical synthesis , Piperazines/chemical synthesis , Receptors, Histamine H3/metabolism , Spiro Compounds/chemical synthesis , Animals , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Azetidines/pharmacology , CHO Cells , Cell Membrane Permeability , Cricetinae , Cricetulus , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Dogs , Histamine H3 Antagonists/pharmacokinetics , Histamine H3 Antagonists/pharmacology , Humans , Learning/drug effects , Madin Darby Canine Kidney Cells , Male , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperazines/pharmacokinetics , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Piperidines/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/genetics , Recognition, Psychology/drug effects , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The medicinal chemistry subgroup of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.
Subject(s)
Chemistry, Pharmaceutical/trends , Drug Discovery/trends , Chemical Engineering/methods , Chemical Engineering/trends , Chemistry, Pharmaceutical/methods , Drug Discovery/methods , Green Chemistry Technology/methods , Green Chemistry Technology/trendsABSTRACT
An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.
Subject(s)
Brain/metabolism , Cannabinoids/agonists , Carbolines/chemistry , Carbolines/pharmacology , Analgesics/chemistry , Analgesics/metabolism , Analgesics/pharmacology , Animals , Brain/drug effects , Carbolines/metabolism , Cell Line , Drug Stability , Humans , Molecular Structure , Pain/drug therapy , Rats , SolubilityABSTRACT
[reaction: see text] The addition of nucleophiles to 3-substituted pyridinium salts prepared from N-methylbenzamide and various pyridines has been investigated. Good to excellent regioselectivities favoring the 2,3-disubstituted 1,2-dihydropyridines were observed. The resulting 1,2-dihydropyridines led to the corresponding 2,3-disubstituted pyridines upon treatment with Mn(OAc)3/NaIO4. This methodology was also successfully applied to the enantioselective syntheses of (-)-L-733,061 and (-)-CP-99,994, two members of a new class of highly potent, nonpeptide, Substance P antagonists.
