ABSTRACT
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
Subject(s)
Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Design , Piperidines/pharmacology , Triazoles/pharmacology , Alzheimer Disease/drug therapy , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Dogs , Humans , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/chemistry , Piperidines/metabolism , Triazoles/chemistry , Triazoles/metabolismABSTRACT
The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers.
Subject(s)
Nerve Tissue Proteins/antagonists & inhibitors , Pyrimidines/pharmacology , TRPC Cation Channels/antagonists & inhibitors , Thiones/pharmacology , Transient Receptor Potential Channels/antagonists & inhibitors , Animals , Calcium Channels , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , TRPA1 Cation Channel , Thiones/chemical synthesis , Thiones/chemistryABSTRACT
In a previous communication, the SAR of a series of potent and selective 5-sulfonyl-benzimidazole CB2-receptor agonists was described. The lack of in vivo activity of compounds from this series was attributed to their poor solubility and metabolic stability. In this Letter, we report on the further optimization of this series, leading to the relatively polar and peripherically acting CB2 agonists 41 and 49. Although both compounds were not active in acute pain models, the less selective compound 41 displayed good, sustained activity in a chronic model of neuropathic pain without the tolerance observed with morphine. In addition, both 41 and 49 delayed the onset of clinical symptoms in an experimental model for Multiple sclerosis.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Multiple Sclerosis/drug therapy , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Animals , Brain/metabolism , Drug Design , Humans , Inflammation , Mice , Models, Chemical , Neuralgia/drug therapy , Rats , Structure-Activity Relationship , Time FactorsABSTRACT
A novel series of benzimidazole CB2-receptor agonists was synthesized and the structure-activity relationship explored. The results showed agonistic activities with an EC(50) up to 0.5 nM and excellent selectivity (>4000-fold) over the CB1 receptor. The size of the substituent on the 2-position determined the level of agonism, ranging from inverse agonism to partial agonism to full agonism, which was more pronounced for the rat CB2 receptor. A wide variation of sulfonyl substituents at the benzimidazole 5-position was tolerated, which was used to optimize the drug-like properties. This resulted into lead compound 14j that can be used to investigate the potential of a selective, peripherically acting CB2 agonist. The in vitro profile of key compounds is displayed using pie bar charts (VlaaiVis).
