ABSTRACT
Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed in sensory neurons where it functions as an irritant sensor for a plethora of electrophilic compounds and is implicated in pain, itch, and respiratory disease. To study its function in various disease contexts, we sought to identify novel, potent, and selective small-molecule TRPA1 antagonists. Herein we describe the evolution of an N-isopropylglycine sulfonamide lead (1) to a novel and potent (4 R,5 S)-4-fluoro-5-methylproline sulfonamide series of inhibitors. Molecular modeling was utilized to derive low-energy three-dimensional conformations to guide ligand design. This effort led to compound 20, which possessed a balanced combination of potency and metabolic stability but poor solubility that ultimately limited in vivo exposure. To improve solubility and in vivo exposure, we developed methylene phosphate prodrug 22, which demonstrated superior oral exposure and robust in vivo target engagement in a rat model of AITC-induced pain.
Subject(s)
Prodrugs/pharmacology , Proline/analogs & derivatives , Proline/pharmacology , Sulfonamides/pharmacology , TRPA1 Cation Channel/antagonists & inhibitors , Animals , Dogs , Drug Discovery , Drug Stability , Humans , Ligands , Madin Darby Canine Kidney Cells , Microsomes, Liver/metabolism , Models, Molecular , Molecular Conformation , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Proline/chemical synthesis , Proline/pharmacokinetics , Rats , Solubility , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , TRPA1 Cation Channel/chemistryABSTRACT
Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation.
Subject(s)
Cyclohexanes/chemistry , Indans/chemistry , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Benzimidazoles/chemistry , Half-Life , Indans/metabolism , Indans/pharmacokinetics , Isomerism , Mice , Protein Binding , Rats , Receptors, Pituitary Hormone/metabolismABSTRACT
Potency with potential: 2-Phenoxy-nicotinamides were identified as potent agonists at the GPBAR1 receptor, a target in the treatment of obesity, type 2 diabetes and metabolic syndrome. Extensive structure-activity relationship studies supported by homology modeling and docking resulted in the identification of optimized GPBAR1 agonists, potent against both human and mouse receptors, endowed with favorable physicochemical properties and good metabolic stability.
Subject(s)
Niacinamide/chemistry , Receptors, G-Protein-Coupled/agonists , Binding Sites , Humans , Molecular Docking Simulation , Niacinamide/metabolism , Protein Binding , Protein Structure, Tertiary , Quinolines/chemistry , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
Subject(s)
Indans/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Crystallography, X-Ray , Humans , Indans/chemistry , Indans/pharmacokinetics , Kinetics , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzodioxoles/chemical synthesis , Imidazoles/chemical synthesis , Nitric Oxide Synthase Type II/metabolism , Pyrimidines/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/therapy , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Cell Line , Chlorocebus aethiops , Crystallography, X-Ray , Dimerization , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Models, Molecular , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Inbred LewABSTRACT
An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported.
