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2.
Bioorg Med Chem Lett ; 24(21): 5111-7, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25437503

ABSTRACT

Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.


Subject(s)
Acetates/chemistry , Acetates/pharmacology , Piperidines/chemistry , Pyrazoles/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Administration, Oral , Animals , Caco-2 Cells , Cell Membrane Permeability/drug effects , Half-Life , Humans , Rats , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 24(21): 5123-6, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25437505

ABSTRACT

Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.


Subject(s)
Acetates/chemistry , Bridged Bicyclo Compounds/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Half-Life , Humans , Indoles/chemistry , Injections, Intravenous , Rats , Rats, Wistar , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity Relationship
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