ABSTRACT
The optimization of a series of 3-carbamoyl 2-pyridone derivatives as CB agonists is reported. These efforts resulted in the discovery of 3-(2-(1-(cyclohexylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxamido)thiazol-4-yl)propanoic acid (21), a potent dual CB1/CB2 agonist without CNS side effects induced by CB1 receptor activation. It exhibited strong inhibition of scratching as a 1.0% acetone solution in the pruritic model.
Subject(s)
Antipruritics/chemistry , Drug Discovery , Pyridones/agonists , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Thiazoles/agonists , Animals , Antipruritics/pharmacology , CHO Cells , Cricetinae , Humans , Mice , Protein Binding/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
The discovery of novel CB2 ligands based on the 3-carbamoyl-2-pyridone derivatives by adjusting the size of side chain at 1-, 5- and 6-position is reported. The structure-activity relationship around this template lead to the identification of S-777469 as a selective CB2 receptor agonist, which exhibited the significant inhibition of scratching induced by Compound 48/80 at 1.0 mg/kg po and 10 mg/kg po (55% and 61%, respectively).
Subject(s)
Antipruritics/chemistry , Antipruritics/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Receptor, Cannabinoid, CB2/agonists , Administration, Oral , Animals , Antipruritics/administration & dosage , CHO Cells , Cricetinae , Disease Models, Animal , Inhibitory Concentration 50 , Ligands , Mice , Mice, Inbred ICR , Molecular Structure , Protein Binding/drug effects , Pyridones/chemistryABSTRACT
Our lead compound 1 showed high affinity for both CB1 and CB2 receptors, suggesting the possibility of inducing psychoactive side effects through the CB1 receptor in the brain. To solve this issue, polar functional groups were introduced at the 3-position of the pyridone core of compound 1 to find CB1/2 dual agonists such as 17 and 20 which did not show any CNS side effects.
Subject(s)
Antipruritics , Central Nervous System/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Animals , Antipruritics/chemistry , Antipruritics/pharmacology , Behavior, Animal , Carbamates/adverse effects , Carbamates/chemistry , Carbamates/pharmacology , Disease Models, Animal , Humans , Mice , Molecular Structure , Pyridones/adverse effectsABSTRACT
The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.
Subject(s)
Aldehydes/chemistry , Imines/chemistry , Ketones/chemistry , Proline/analogs & derivatives , Pyrrolidines/chemistry , Catalysis , Molecular Structure , Proline/chemistry , StereoisomerismABSTRACT
Dihydroxyacetone variants have been explored as donors in organocatalytic aldol reactions with various aldehyde and ketone acceptors. The protected form of dihydroxyacetone that was chosen for in-depth study was 2,2-dimethyl-1,3-dioxan-5-one, 1. Among the catalysts surveyed here, proline proved to be superior in terms of yield and stereoselectivities in the construction of various carbohydrate scaffolds. In a fashion analogous to aldolase enzymes, the de novo preparation of L-ribulose, L-lyxose, D-ribose, D-tagatose, 1-amino-1-deoxy-D-lyxitol, and other carbohydrates was accomplished via the use of 1 and proline. In reactions using 2,2-dimethyl-1,3-dioxan-5-one 1 as a donor, (S)-proline can be used as a functional mimic of tagatose aldolase, whereas (R)-proline can be regarded as an organocatalytic mimic of fuculose aldolase.
Subject(s)
Aldehyde-Lyases/chemistry , Aldehyde-Lyases/metabolism , Carbohydrates/chemical synthesis , Dihydroxyacetone/analogs & derivatives , Dihydroxyacetone/chemistry , Dioxanes , Hexoses/chemistry , Hexoses/metabolism , Molecular StructureABSTRACT
The development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings (1-5 mol %) is reported. Based on principles gained from the study of (S)-proline-catalyzed Mannich-type reactions that afford enantiomerically enriched syn-products, (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (RR35) has been designed to catalyze the direct enantioselective anti-selective Mannich-type reactions. Computational studies of the above reaction using HF/6-31G* level of theory suggested that this design would be highly effective. The catalyst was subsequently synthesized and studied in organocatalytic Mannich-type reactions between unmodified aldehydes and N-PMP-protected alpha-imino esters. In accord with the design principles and in quantitative agreement with the theoretical predictions, reactions catalyzed by this catalyst afforded anti-products in good yields with excellent diastereo- and enantioselectivities (anti:syn 94:6 to 98:2, >97 to >99% ee).
Subject(s)
Aldehydes/chemistry , Amino Acids/chemistry , Catalysis , Imidazoles/chemistry , Proline/chemistry , Pyrrolidines/chemistryABSTRACT
Prostaglandin (PG) D(2), the major cyclooxygenase metabolite generated from immunologically stimulated mast cells, is thought to contribute to the pathogenesis of allergic diseases due to its various inflammatory effects. However, the lack of PGD(2) (DP) receptor antagonists has limited the study of its essential roles in the disease state. Recent discoveries of several DP receptor antagonists, the development of the mutant mouse and the discovery of a second PGD(2) receptor, CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor, have revealed the crucial roles of PGD(2) and CRTH2 receptors in allergic disorders. This review presents biological evidence that PGD(2) plays an essential role in allergy disorders and discusses the therapeutic possibilities of recently reported PGD(2) antagonists.
Subject(s)
Anti-Allergic Agents/pharmacology , Hypersensitivity/drug therapy , Prostaglandin D2/antagonists & inhibitors , Animals , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/therapeutic use , Humans , Ligands , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
Novel prostaglandin D(2) (PGD(2)) receptor antagonists were synthesized as a potential new class of antiallergic agents having a bicyclo[2.2.1]heptane ring system with sulfonamide groups. Some of them exhibit extremely potent antagonism of the PGD(2) receptor in radioligand binding and cAMP formation assays with IC(50) values below 50 nM and much less antagonism of TXA(2) and PGI(2) receptors. These potent PGD(2) receptor antagonists, when given orally, dramatically suppress various allergic inflammatory responses such as increased vascular permeability in allergic rhinitis, conjunctivitis, and asthma models. The excellent pharmacological profiles of PGD(2) receptor antagonists, originally synthesized in our laboratories, are of potentially great clinical significance. This study also provides experimental evidence suggesting that PGD(2) plays an important role in the pathogenesis of allergic diseases.
Subject(s)
Anti-Allergic Agents/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Hexanes/chemical synthesis , Prostaglandin D2/metabolism , Receptors, Immunologic , Receptors, Prostaglandin/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Airway Obstruction/drug therapy , Airway Obstruction/immunology , Animals , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacology , Blood Platelets/drug effects , Blood Platelets/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Capillary Permeability/drug effects , Conjunctiva/blood supply , Cyclic AMP/biosynthesis , Guinea Pigs , Hexanes/chemistry , Hexanes/pharmacology , Humans , In Vitro Techniques , Radioligand Assay , Receptors, Epoprostenol , Receptors, Thromboxane/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
In an earlier paper, we reported that novel prostaglandin D(2) (PGD(2)) receptor antagonists having the bicyclo[2.2.1]heptane ring system as a prostaglandin skeleton were a potent new class of antiallergic agents and suppressed various allergic inflammatory responses such as those observed in conjunctivitis and asthma models. In the present study, we synthesized PGD(2) receptor antagonists having the 6,6-dimethylbicyclo[3.1.1]heptane ring system. These derivatives have the amide moiety, in contrast to those with the bicyclo[2.2.1]heptane ring system, which have the sulfonamide group. The derivatives having the 6,6-dimethylbicyclo[3.1.1]heptane ring also exhibited strong activity in PGD(2) receptor binding and cAMP formation assays. In in vivo assays such as allergic rhinitis, conjunctivitis, and asthma models, these series of derivatives showed excellent pharmacological profiles. In particular, compound 45 also effectively suppressed eosinophil infiltration in allergic rhinitis and asthma models. This compound (45, S-5751) is now being developed as a promising alternative antiallergic drug candidate.
Subject(s)
Anti-Allergic Agents/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Heptanes/chemical synthesis , Prostaglandin D2/metabolism , Receptors, Immunologic , Receptors, Prostaglandin/antagonists & inhibitors , Thiophenes/chemical synthesis , Administration, Oral , Airway Obstruction/drug therapy , Airway Obstruction/immunology , Animals , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacology , Asthma/drug therapy , Asthma/immunology , Asthma/pathology , Blood Platelets/drug effects , Blood Platelets/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Capillary Permeability/drug effects , Conjunctiva/blood supply , Cyclic AMP/biosynthesis , Eosinophils/pathology , Guinea Pigs , Heptanes/chemistry , Heptanes/pharmacology , Humans , Radioligand Assay , Rhinitis, Allergic, Perennial/drug therapy , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Perennial/pathology , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
We achieved a total synthesis of terprenin, a novel potent immunoglobulin E antibody suppressant which was obtained from the fermentation broth of Aspergillus candidus RF-5672 and has a highly oxygenated p-terphenyl skeleton with a prenyloxy side chain. The key steps relied on the Suzuki reaction to construct the terphenyl skeleton and on regioselective halogenations to selectively combine the aromatic rings. The highly efficient and practical production of this important natural product offers promise for the development of a new type of antiallergic drug.
ABSTRACT
Regioselective halogenations and Suzuki reactions ensure proper linkage of the aromatic rings in two total syntheses of terprenin (1). Both routes make it possible to prepare 1 efficiently and in large quantity.
