ABSTRACT
A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Integrins/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Crohn Disease/drug therapy , Disease Models, Animal , Half-Life , Humans , Integrin alpha4beta1/metabolism , Integrins/metabolism , Jurkat Cells , Microsomes, Liver/metabolism , RatsABSTRACT
The bradykinin B(1) receptor plays a critical role in chronic pain and inflammation, although efforts to demonstrate efficacy of receptor antagonists have been hampered by species-dependent potency differences, metabolic instability, and low oral exposure of current agents. The pharmacology, pharmacokinetics, and analgesic efficacy of the novel benzamide B(1) receptor antagonist 7-chloro-2-[3-(9-pyridin-4-yl-3,9-diazaspiro[5.5]undecanecarbonyl)phenyl]-2,3-dihydro-isoindol-1-one (ELN441958) is described. ELN441958 competitively inhibited the binding of the B(1) agonist ligand [(3)H]desArg(10)-kallidin ([(3)H]DAKD) to IMR-90 human fibroblast membranes with high affinity (K(i) = 0.26 +/- 0.02 nM). ELN441958 potently antagonized DAKD (but not bradykinin)-induced calcium mobilization in IMR-90 cells, indicating that it is highly selective for B(1) over B(2) receptors. Antagonism of agonist-induced calcium responses at B(1) receptors from different species indicated that ELN441958 is selective for primate over rodent B(1) receptors with a rank order potency (K(B), nanomolar) of human (0.12 +/- 0.02) approximately rhesus monkey (0.24 +/- 0.01) > rat (1.5 +/- 0.4) > mouse (14 +/- 4). ELN441958 had good permeability and metabolic stability in vitro consistent with high oral exposure and moderate plasma half-lives in rats and rhesus monkeys. Because ELN441958 is up to 120-fold more potent at primate than at rodent B(1) receptors, it was evaluated in a primate pain model. ELN441958 dose-dependently reduced carrageenan-induced thermal hyperalgesia in a rhesus monkey tail-withdrawal model, with an ED(50) approximately 3 mg/kg s.c. Naltrexone had no effect on the antihyperalgesia produced by ELN441958, indicating a lack of involvement of opioid receptors. ELN441958 is a novel small molecule bradykinin B(1) receptor antagonist exhibiting high oral bioavailability and potent systemic efficacy in rhesus monkey inflammatory pain.
Subject(s)
Analgesics/pharmacology , Bradykinin B1 Receptor Antagonists , Spiro Compounds/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Analgesics/chemistry , Analgesics/pharmacokinetics , Animals , Bradykinin/analogs & derivatives , Bradykinin/pharmacology , Calcium/metabolism , Carrageenan/toxicity , Cell Line , Cell Membrane Permeability , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Kallidin/analogs & derivatives , Kallidin/metabolism , Kallidin/pharmacology , Macaca mulatta , Mice , Mice, Knockout , Microsomes, Liver/metabolism , Molecular Structure , Naltrexone/pharmacology , Naproxen/pharmacology , Naproxen/therapeutic use , Narcotic Antagonists , Rats , Receptor, Bradykinin B1/genetics , Receptor, Bradykinin B1/metabolism , Species Specificity , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , TransfectionABSTRACT
To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.
