ABSTRACT
Central heteroaryl ring analogues belonging to a series of potent hydroxamate TACE inhibitors were synthesized. The TACE inhibitory activities of these compounds were evaluated by in vitro WBA and in silico molecular modeling studies using crystal structure of human TACE. Compound 14 showed very good in vitro inhibition, supported by the in silico docking studies.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Chemistry Techniques, Synthetic , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Models, Molecular , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , ADAM Proteins/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Drug Discovery , Humans , Hydroxamic Acids/chemistry , Protease Inhibitors/chemistry , Protein Conformation , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
OBJECTIVE: These studies aimed to outline the in vitro and in vivo histamine H(1) receptor antagonistic activity and safety pharmacology of SUN-1334H, a new potent antihistamine agent under clinical development. METHODS: In vitro antihistamine activity and selectivity of SUN-1334H was evaluated in a panel of receptor and enzyme assays and functional assays using isolated tissues. In vivo antihistamine and antiallergy efficacy were assessed following oral administration of SUN-1334H in histamine-induced bronchoconstriction in guinea pigs, skin wheal in beagle dogs and ovalbumin-induced rhinitis (sneezing, vascular permeability and intranasal pressure) in guinea pigs. Cardiovascular safety was assessed by CHO-K1/human ether-à-go-go related gene (hERG) K(+) current assay, dog telemetry and guinea-pig ECG. CNS safety was assessed by functional observational battery in rats and pentobarbital-induced sedation and pentylenetetrazol-induced convulsions in mice. The effect on intestinal motility was assessed in rats. RESULTS: In vitro receptor binding assays showed that SUN-1334H had high histamine H(1) receptor binding affinity with an inhibition constant value of 9.7 nmol/L and either no or insignificant affinity with a panel of receptors and enzymes. In functional assays, SUN-1334H caused potent inhibition of histamine-induced contractions of isolated guinea-pig ileum with an IC(50) (half the maximal inhibitory concentration) of 0.198 micromol/L. In contrast, SUN-1334H had no significant effect on isolated tissue contractions induced by cholinergic, H(2)-histaminergic, serotonergic, adrenergic receptor agonists or BaCl(2). In studies of animal models of histamine-mediated disorders, SUN-1334H potently inhibited histamine-induced bronchospasm over 24 hours following oral administration and completely suppressed histamine-induced skin wheal in beagle dogs and ovalbumin-induced rhinitis in guinea pigs. In CHO-K1/hERG cells, SUN-1334H did not modulate hERG K(+)-currents at concentrations as high as 100 micromol/L. Cardiovascular and CNS function and intestinal motility were not altered at doses several-fold greater than those required for efficacy, indicating a good safety profile of the drug. CONCLUSIONS: SUN-1334H is a potent, orally active, highly selective H(1) receptor antagonist with a long duration of action in its preclinical profile. It has potential for the treatment of disorders involving histamine as a mediator.
