ABSTRACT
A screening hit was used as the basis for the core structure of a new series of acylglycinamide GlyT-1 inhibitors. Investigation of the SAR around four areas of diversity used facile chemistry to prepare compounds quickly. By focussing on reducing the lipophilicity and improving the aqueous solubility in the series we were able to prepare a compound (17e) with a good level of activity at GlyT-1, selectivity over GlyT-2 and moderate oral bioavailability.
Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Glycine/analogs & derivatives , Animals , Glycine/chemistry , Glycine/metabolism , Glycine/pharmacokinetics , Glycine/pharmacology , Glycine Plasma Membrane Transport Proteins/metabolism , Humans , Inhibitory Concentration 50 , Rats , Solubility , Structure-Activity RelationshipABSTRACT
The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.
Subject(s)
Brain/drug effects , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Brain/metabolismABSTRACT
A high-throughput screen targeting the EP(1) receptor identified non-acidic glycine sulfonamide derivative 2a with a pK(i) of 6.2. Analogue synthesis allowed a thorough investigation of the structure-activity relationship (SAR) and led to a 100-fold increase in recombinant potency.
Subject(s)
Glycine Agents/chemical synthesis , Glycine Agents/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , CHO Cells , Cell Membrane/metabolism , Chromatography, High Pressure Liquid , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme System/metabolism , Dinoprostone/metabolism , Drug Evaluation, Preclinical , Humans , Indicators and Reagents , Receptors, Prostaglandin E, EP1 SubtypeABSTRACT
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.
