ABSTRACT
Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).
Subject(s)
Acetates/pharmacology , Drug Discovery , Indoleacetic Acids/pharmacology , Indoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Humans , Indoleacetic Acids/chemistry , Indoles/chemistry , Neutrophils/drug effectsABSTRACT
A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34.
Subject(s)
Acetates/chemical synthesis , Receptors, Immunologic/agonists , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/agonists , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Acetates/pharmacology , Animals , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
The identification of two novel series of formyl peptide receptor 1 (FPR1) antagonists are reported, represented by methionine benzimidazole 6 and diamide 7. Both series specifically inhibited the binding of labelled fMLF to hrFPR1 and selectively antagonized FPR1 function in human neutrophils, making them useful in vitro validation tools for the target.
Subject(s)
Drug Discovery , Receptors, Formyl Peptide/antagonists & inhibitors , Receptors, Formyl Peptide/chemistry , Humans , Molecular StructureABSTRACT
We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.
Subject(s)
Isoxazoles/chemical synthesis , Monocarboxylic Acid Transporters/antagonists & inhibitors , Monocarboxylic Acid Transporters/chemistry , Naphthalenes/chemical synthesis , Pyrrolidines/chemical synthesis , Quinolines/chemical synthesis , Symporters/antagonists & inhibitors , Symporters/chemistry , Thiazolidines/chemical synthesis , Isomerism , Isoxazoles/chemistry , Kinetics , Magnetic Resonance Spectroscopy , Molecular Conformation , Naphthalenes/chemistry , Pyrrolidines/chemistry , Quinolines/chemistry , Thiazolidines/chemistryABSTRACT
Lithiation of N-benzyl pyridine and quinoline carboxamides alpha to nitrogen gives anions that undergo intramolecular attack on the pyridine or quinoline ring, either directly or on activation of the ring by N-acylation. The resulting four-, five-, or six-membered-ring-containing compound may be oxidized, protonated, alkylated, or acylated to give a range of polycyclic heterocycles, including pyrrolopyridines, pyrroloquinolines, benzonaphthyridines, and azaspirocyclic beta-lactams. [reaction: see text]
