ABSTRACT
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.
Subject(s)
Carboxylic Acids/chemical synthesis , Naphthalenes/chemical synthesis , Purinergic P2 Receptor Antagonists/chemical synthesis , Receptors, Purinergic P2 , Uridine Diphosphate , Animals , Binding, Competitive , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacokinetics , Carboxylic Acids/pharmacology , Mice , Molecular Structure , Naphthalenes/chemistry , Naphthalenes/pharmacokinetics , Naphthalenes/pharmacology , Pan troglodytes , Protein Binding/drug effects , Purinergic P2 Receptor Antagonists/chemistry , Purinergic P2 Receptor Antagonists/pharmacokinetics , Purinergic P2 Receptor Antagonists/pharmacology , Receptors, Purinergic P2Y , Structure-Activity RelationshipABSTRACT
A weak antagonist of the pyrimidinergic receptor P2Y(14) containing a dihydropyridopyrimidine core was identified through high-throughput screening. Subsequent optimization led to potent, non-UTP competitive antagonists and represent the first reported non-nucleotide antagonists of this receptor. Compound 18q was identified as a 10 nM P2Y(14) antagonist with good oral bioavailability and provided sufficient exposure in mice to be used as a tool for future in vivo studies.
Subject(s)
Purinergic P2 Receptor Antagonists/chemical synthesis , Pyrimidines/chemical synthesis , Receptors, Purinergic P2/chemistry , Administration, Oral , Animals , Biological Availability , Mice , Molecular Structure , Pan troglodytes , Purinergic P2 Receptor Antagonists/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Receptors, Purinergic P2Y , Structure-Activity RelationshipABSTRACT
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.
Subject(s)
Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Cyclopropanes/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Receptors, Prostaglandin E/antagonists & inhibitors , Succinimides/chemistry , Carboxylic Acids/chemistry , Chemistry, Organic/instrumentation , Chemistry, Pharmaceutical/instrumentation , Crystallization , Cyclopropanes/chemistry , Drug Design , Electronics , Heterocyclic Compounds, 3-Ring/chemistry , Models, Chemical , Molecular Structure , Receptors, Prostaglandin E, EP4 Subtype , Stereoisomerism , Sulfonamides/chemistry , Technology, PharmaceuticalABSTRACT
A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.
Subject(s)
Hydrocarbons, Halogenated/chemical synthesis , Hydrocarbons, Halogenated/pharmacology , Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Animals , Combinatorial Chemistry Techniques , Diabetes Mellitus/chemically induced , Disease Models, Animal , Drug Design , Drug Screening Assays, Antitumor , Haplorhini , Hydrocarbons, Halogenated/chemistry , Mice , Molecular Structure , Naphthalenes/chemistry , Neoplasms/chemically induced , Organophosphonates/chemistry , RatsABSTRACT
A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.
Subject(s)
Arthritis, Experimental/drug therapy , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Prostaglandin E/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Arthritis, Experimental/chemically induced , Dogs , Guinea Pigs , Humans , Macaca mulatta , Molecular Structure , Quinolines/pharmacokinetics , Rats , Receptors, Prostaglandin E, EP4 Subtype , Structure-Activity Relationship , Sulfonamides/pharmacokineticsABSTRACT
Two different series of very potent and selective EP(3) antagonists have been reported: a novel series of ortho-substituted cinnamic acids [Belley, M., Gallant, M., Roy, B., Houde, K., Lachance, N., Labelle, M., Trimble, L., Chauret, N., Li, C., Sawyer, N., Tremblay, N., Lamontagne, S., Carrière, M.-C., Denis, D., Greig, G. M., Slipetz, D., Metters, K. M., Gordon, R., Chan, C. C., Zamboni, R. J. Bioorg. Med. Chem. Lett.2005, 15, 527] and the acylsulfonamides of ortho-(arylmethyl)cinnamates. [(a) Juteau, H., Gareau, Y., Labelle, M., Sturino, C. F., Sawyer, N., Tremblay, N., Lamontagne, S., Carrière, M.-C., Denis, D., Metters, K. M. Bioorg. Med. Chem. 2001, 9, 1977; (b) Juteau, H., Gareau, Y., Labelle, M., Lamontagne, S., Tremblay, N., Carrière, M.-C., Denis, D., Sawyer, N., Metters, K. M. Bioorg. Med. Chem. Lett.2001, 11, 747] The structural differences between the two series, along with their biological activity in vivo, in vitro, and metabolism, are analyzed. Some of those compounds, including hybrids containing the best structural features of both series, possess K(i) as low as 0.6 nM on the EP(3) receptor.
Subject(s)
Cinnamates/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/pharmacology , Cinnamates/chemistry , Humans , Sulfonamides/chemistryABSTRACT
A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.
Subject(s)
Cinnamates/chemical synthesis , Cinnamates/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Cell Line , Cinnamates/metabolism , Cyclic AMP/biosynthesis , Humans , Pharmacokinetics , Protein Binding , Receptors, Prostaglandin E, EP2 Subtype , Receptors, Prostaglandin E, EP3 Subtype , Structure-Activity RelationshipABSTRACT
Potent and selective ligands for the human EP3 prostanoid receptor are described. Triaryl compounds bearing an ortho-substituted propionic acid moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinities of key compound on all eight human prostanoid receptors is reported.