ABSTRACT
A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting from the prostacyclin derivative 5b, a nonselective agonist for prostaglandin receptors, replacement of the core structure with an octahydro-2H-cyclopenta[b]oxepine scaffold led to the discovery of the potent and selective FP and EP3 dual agonist 11b as a lead compound for the development of an antiglaucoma agent.
ABSTRACT
To identify structurally novel corticotropin-releasing factor 1 (CRF(1)) receptor antagonists, a series of bicyclic core analogs pyrrolo[1,2-b]pyridazines and pyrrolo[2,1-f]triazin-4(3H)-ones, which were designed based on a monocyclic core antagonist, was synthesized and evaluated. Among the compounds tested, 2-difluoromethoxy-4-methylpyridin-5-yl analog 27 was found to show efficacy in a dose-dependent manner in an elevated plus maze test in rats. The discovery process and structure-activity relationship is presented.
Subject(s)
Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Pyridazines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Triazines/chemistry , Triazines/pharmacology , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/pharmacokinetics , Male , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/metabolism , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/pharmacokineticsABSTRACT
To identify structurally novel CRF1 receptor antagonists, a series of bicyclic core antagonists, pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines, imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines were designed, synthesized and evaluated as CRF1 receptor antagonists. Compounds 2-27 showed binding affinity (IC(50)=4.2-418 nM) and antagonist activity (EC(50)=4.0-889 nM). Compound 5 was found to show oral efficacy in an Elevated Plus Maze test in rats. Further chemical modification of them led us to discovery of the tricyclic core antagonists pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidines. The discovery process of these compounds is presented, as is the study of the structure-activity relationship.
Subject(s)
Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Receptors, Corticotropin-Releasing Hormone/chemistry , Animals , Humans , Kinetics , Male , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
To identify an orally active corticotropin-releasing factor 1 receptor antagonist, a series of 6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives were designed, synthesized and evaluated. An in vitro study followed by in vivo and pharmacokinetic studies of these heterotricyclic compounds led us to the discovery of an orally active CRF1 receptor antagonist. The results of a structure-activity relationship study are presented.
Subject(s)
Pyrazoles/pharmacology , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Drug Design , Male , Maze Learning/drug effects , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , SwineABSTRACT
A series of 3-(2-aminocarbonylphenyl)propanoic acid analogs possessing the (1R)-1-(3,5-dimethylphenyl)-3-methylbutylamine moiety on the carboxyamide side chain were synthesized and evaluated for their binding affinity for the EP1-4 receptors and their antagonist activity for the EP3 receptor. Rational drug design based on the structure of the metabolites in human liver microsomes led us to the discovery of another series of analogs. Several compounds were further evaluated for their in vivo efficacy in rats after oral administration and also for their pharmacokinetic profiles including in vitro stability in the liver microsomes.
Subject(s)
Microsomes, Liver/metabolism , Propionates , Receptors, Prostaglandin E/antagonists & inhibitors , Administration, Oral , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Drug Stability , Female , Humans , Microsomes, Liver/chemistry , Molecular Structure , Phenyl Ethers , Pregnancy , Pregnancy, Animal , Propionates/chemical synthesis , Propionates/chemistry , Radioligand Assay , Rats , Receptors, Prostaglandin E/metabolism , Receptors, Prostaglandin E, EP3 SubtypeABSTRACT
A series of novel N-acylsulfonamide analogs were synthesized and evaluated for their binding affinity and antagonist activity for the EP3 receptor subtype. Representative compounds were also evaluated for their inhibitory effect on PGE(2)-induced uterine contraction in pregnant rats. Among those tested, a series of N-acylbenzenesulfonamide analogs were found to be more potent than the corresponding carboxylic acid analogs in both the in vitro and in vivo evaluations. The structure activity relationships (SAR) are also discussed.
Subject(s)
Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/pharmacology , Animals , Dinoprostone/pharmacology , Drug Discovery , Female , Pregnancy , Rats , Receptors, Prostaglandin E, EP3 Subtype , Structure-Activity Relationship , Sulfonamides/chemistry , Uterine Contraction/drug effectsABSTRACT
A series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs were synthesized and evaluated for their in vitro potency. In most cases, introduction of one or two substituents into the two phenyl moieties resulted in the tendency of an increase or retention of in vitro activities. Several compounds, which showed excellent subtype selectivity, were evaluated for their inhibitory effect against PGE(2)-induced uterine contraction in pregnant rats, which is thought to be mediated by the EP3 receptor subtype. The structure-activity relationships (SARs) are also discussed.
Subject(s)
Propionates/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Cricetulus , Female , Magnetic Resonance Spectroscopy , Mass Spectrometry , Pregnancy , Propionates/chemistry , Propionates/pharmacokinetics , Rats , Receptors, Prostaglandin E, EP3 Subtype , Uterine Contraction/drug effectsABSTRACT
A series of 3-(2-aminocarbonyl-4-phenoxymethylphenyl)propanoic acid analogs were synthesized and evaluated for their EP3 antagonist activity in the presence of additive serum albumin. Several compounds were biologically evaluated for their in vivo efficacy with respect to the PGE(2)-induced uterine contraction in pregnant rats as well as their pharmacokinetics. The discovery process of these potent and selective EP3 antagonists and their structure activity relationship are also presented.
Subject(s)
Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Prostaglandin E/metabolism , Uterine Contraction/drug effects , Animals , CHO Cells , Cattle , Cricetinae , Cricetulus , Female , Mice , Phenyl Ethers , Pregnancy , Propionates/chemistry , Rats , Receptors, Prostaglandin E, EP3 Subtype , Serum Albumin, Bovine/metabolismABSTRACT
A series of acrylic acids and their structurally related compounds were evaluated for their binding affinity to four EP receptor subtypes (EP1-4). Starting from the initial hit 3, which was discovered in our in-house library, compounds 4 and 5 were identified as new chemical leads as candidates for further optimization towards a selective EP3 receptor antagonist. The identification process of these compounds and their pharmacokinetic profiles are presented.
Subject(s)
Acrylates/chemistry , Acrylates/pharmacology , Pyrazoles/chemistry , Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Prostaglandin E/metabolism , Acrylates/pharmacokinetics , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Humans , Mice , Microsomes, Liver/metabolism , Molecular Structure , Protein Binding , Rats , Receptors, Prostaglandin E, EP3 Subtype , Structure-Activity RelationshipABSTRACT
The absolute configuration was determined for the title compound, (-)-C(32)H(56)O(6)S(2)Si, (I), which was prepared in a synthetic study on the natural products bryostatins. Two independent molecules show similar conformations, except for the orientation of the methoxy groups.
ABSTRACT
The absolute configuration was determined for the title compound, (+)-C(18)H(24)O(3)S, (I), which was prepared in a synthetic study on the natural products, bryostatins.