ABSTRACT
The complement system represents an innate immune mechanism of host defense that has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the biological activity of C5a and its classical receptor have been widely studied. Because specific antagonism of the C5aR could have therapeutic benefit without affecting the protective immune response, the C5aR continues to be a promising target for pharmaceutical research. The lack of specific, potent and orally bioavailable small-molecule antagonists has limited the clinical investigation of the C5aR. We report the discovery of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a small-molecule, orally bioavailable, selective, and potent inverse agonist of the human C5aR. NDT 9513727 was discovered based on the integrated use of in vitro affinity and functional assays in conjunction with medicinal chemistry. NDT 9513727 inhibited C5a-stimulated responses, including guanosine 5'-3-O-(thio)triphosphate binding, Ca(2+) mobilization, oxidative burst, degranulation, cell surface CD11b expression and chemotaxis in various cell types with IC(50)s from 1.1 to 9.2 nM, respectively. In C5a competition radioligand binding experiments, NDT 9513727 exhibited an IC(50) of 11.6 nM. NDT 9513727 effectively inhibited C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. The findings suggest that NDT 9513727 may be a promising new entity for the treatment of human inflammatory diseases.
Subject(s)
Benzodioxoles/pharmacology , Imidazoles/pharmacology , Receptor, Anaphylatoxin C5a/agonists , Animals , CD11b Antigen/drug effects , Calcium Signaling/drug effects , Cell Degranulation/drug effects , Cell Line , Chemotaxis/drug effects , Gerbillinae , Humans , Macaca , Neutropenia/chemically induced , Protein Binding , Respiratory Burst/drug effectsABSTRACT
A series of novel 1H-pyrazolo-[3,4-c]cyclophepta[1,2-c]thiophenes was prepared and screened at selected dopamine receptor subtypes. Compound 4 (NGB 4420) displayed high affinity and selectivity (>100-fold) for the D(4) over D(2) and other CNS receptors. This compound was identified as a D(4) antagonist via its attenuation of dopamine agonist-induced GTPgamma(35)S binding at D(4) receptor.
Subject(s)
Receptors, Dopamine D2/metabolism , Thiophenes/metabolism , Dopamine Antagonists/metabolism , Dopamine Antagonists/pharmacology , Humans , Ligands , Protein Binding , Receptors, Dopamine D4 , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
5-piperazinyl-1,2,6,7-tetrahydro-5H-azepino[3,2,1-hi]indol-4-one derivatives were designed, synthesized, and identified as a new series of mixed dopamine D(2)/D(4) receptor antagonists. This series featured a rigid tricyclic ring system as an important pharmacophore core structure for high binding affinity. Molecular modeling studies are also described.
Subject(s)
Dopamine D2 Receptor Antagonists , Indoles/chemical synthesis , Indoles/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Molecular , Monte Carlo Method , Protein Binding , Radioligand Assay , Receptors, Dopamine D4 , Structure-Activity RelationshipABSTRACT
Optimization of the lead compound 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2,3-dihydro-indol-1-yl)-ethanone 1 by systematic structure-activity relation (SAR) studies lead to two potent compounds 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 2n and 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 7b. Their related synthesis was also reported.
Subject(s)
Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Indoles/chemical synthesis , Indoles/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Animals , Binding, Competitive/drug effects , Glycine/chemistry , Humans , In Vitro Techniques , Prazosin/metabolism , Rats , Receptors, Dopamine D4 , Recombinant Proteins/drug effects , Structure-Activity RelationshipABSTRACT
A series of chiral benzylpiperazinyl-1-(2,3-dihydro-indol-1-yl)ethanone derivatives were prepared and examined for their affinity at dopamine D(2) and D(4) receptors. Three compounds having D(2)/D(4) affinity ratios approximating that found for the atypical neuroleptic clozapine were further evaluated in behavioral tests of antipsychotic efficacy and motor side effects.