ABSTRACT
A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2â¯=â¯1.1â¯nM, EP3â¯=â¯1.0â¯nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01â¯mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.
Subject(s)
Receptors, Prostaglandin E, EP2 Subtype/agonists , Receptors, Prostaglandin E, EP3 Subtype/agonists , Thiazoles/pharmacology , Animals , Caco-2 Cells , Cell Membrane Permeability/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Haplorhini , Humans , Male , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
The cyclic carbamate derivatives, 2-{[2-((4S)-4-{(1E,3R)-8-fluoro-3-hydroxy-4,4-dimethyl-1-octenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid (5) and 2-{[2-((4S)-4-{(1E,3R)-3-[1-(4-fluorobutyl)cyclobutyl]-3-hydroxy-1-propenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid (7) were identified as the first potent dual EP2 and EP3 agonists with selectivity against the EP1 and EP4 subtypes. Compounds 5 and 7 demonstrated highly potent dual EP2 and EP3 agonist activity with EC50 values of 10nM or less. In addition, these compounds possess structural features distinct from natural prostaglandins, such as a cyclic carbamate moiety, a dimethyl or cyclobutyl group and a terminal fluorine atom.
Subject(s)
Carboxylic Acids/chemistry , Receptors, Prostaglandin E, EP2 Subtype/agonists , Receptors, Prostaglandin E, EP3 Subtype/agonists , Animals , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacokinetics , Half-Life , Humans , Kinetics , Mice , Protein Binding , Rats , Receptors, Prostaglandin E, EP1 Subtype/agonists , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Receptors, Prostaglandin E, EP2 Subtype/metabolism , Receptors, Prostaglandin E, EP3 Subtype/metabolism , Receptors, Prostaglandin E, EP4 Subtype/agonists , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Structure-Activity RelationshipABSTRACT
An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.
Subject(s)
Asthma/drug therapy , Butyrates/pharmacology , Butyrates/therapeutic use , Indoles/pharmacology , Indoles/therapeutic use , Leukotriene Antagonists/pharmacology , Leukotriene Antagonists/therapeutic use , Receptors, Leukotriene/drug effects , Animals , Biological Availability , Dogs , Guinea Pigs , Humans , Leukotriene Antagonists/pharmacokinetics , RatsABSTRACT
A potent, orally available dual CysLT1 and CysLT2 receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{(E)-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1H-indol-1-yl)butanoic acid (15: ONO-4310321, IC50: CysLT1=13nM, CysLT2=25 nM) showed excellent pharmacokinetic profiles (%Frat=100) compared with our previously reported compound 1 (%Frat=1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (%Frat⩾40) in rats (HBDs: ⩽2, ClogP: >6.5 and TPSA: <100). Especially, reduction of only one hydrogen-bond donor (HBDs) showed dramatically improved oral bioavailability. This small change of HBDs in dicarboxylic acid derivatives is generally a very effective modification.
Subject(s)
Dicarboxylic Acids/administration & dosage , Dicarboxylic Acids/pharmacology , Drug Discovery , Leukotriene Antagonists/administration & dosage , Leukotriene Antagonists/pharmacology , Receptors, Leukotriene/metabolism , Administration, Oral , Animals , Biological Availability , CHO Cells , Caco-2 Cells , Cricetulus , Dicarboxylic Acids/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Leukotriene Antagonists/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
4-{[2-[(2-Furylsulfonyl)(isobutyl)amino]-5-(trifluoromethyl)phenoxy]methyl}benzoic acid analogs 2a and b and a series of the acid analogs, in which the carboxylic acid residue of 2b was replaced with various kinds of carboxylic acid bioisosteres, were synthesized and evaluated as EP1 receptor antagonists. Compound 2b and its monocyclic acid analogs, in which the carboxylic acid residue of 2b was replaced with monocyclic acid bioisosteres, were found to show potent EP1 receptor antagonist activity. Optimization of the linker Y between the phenyl moiety and the carboxylic acid residue of 2b was also carried out (Table 5). Compounds 2b and 16 and 17 possessing conformationally restricted linker Y were found to show the most optimized potency among the tested compounds. Cytochrome P450 inhibition of optimized compounds was also investigated. Details of the structure-activity relationship study are presented.
