ABSTRACT
We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
Subject(s)
Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacokinetics , Indoles/pharmacokinetics , Integrin alpha4beta1/antagonists & inhibitors , Pyrrolidines/pharmacokinetics , Administration, Oral , Animals , Biological Availability , CHO Cells , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/pharmacology , Dogs , Guinea Pigs , Haplorhini , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Mice , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.
Subject(s)
Benzoates/pharmacology , Integrin alpha4beta1/antagonists & inhibitors , Pyrroles/pharmacology , Administration, Oral , Animals , Anti-Inflammatory Agents/pharmacology , Asthma/drug therapy , Benzoates/administration & dosage , Benzoates/chemical synthesis , Cells, Cultured , Disease Models, Animal , Dogs , Female , Inhibitory Concentration 50 , Mice , Mice, Inbred BALB C , Permeability , Pyrroles/administration & dosage , Pyrroles/chemical synthesis , RatsABSTRACT
A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL=18.5 ml/min/kg,F=28%; rats, CL=5.2 ml/min/kg,F=36%; dogs, CL=3.6 ml/min/kg,F=55%). Additionally, 12l exhibited potent activity with an IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model.
Subject(s)
Benzoates/chemical synthesis , Benzoates/pharmacokinetics , Integrin alpha4beta1/antagonists & inhibitors , Administration, Oral , Animals , Benzoates/pharmacology , Disease Models, Animal , Dogs , Inflammation/drug therapy , Inhibitory Concentration 50 , Mice , Pharmacokinetics , Pleurisy/drug therapy , Rats , Structure-Activity RelationshipABSTRACT
A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50 = 1.6 nM each) and moderate lipophilicity (Log D = 2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.
