title: Preclinical efficacy and safety pharmacology of SUN-1334H, a potent orally active antihistamine agent.
abstract: 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.
authors.affiliation: Sun Pharma Advanced Research Company Limited, Atladara, Vadodara, Gujarat, India. sanjay.mandhane@sunpharma.com
authors.forename: Sanjay N
authors.initials: SN
authors.lastname: Mandhane
authors.forename: Upendra B
authors.initials: UB
authors.lastname: Ayer
authors.forename: Ajay S
authors.initials: AS
authors.lastname: Midha
authors.forename: Chitturi Trinadha
authors.initials: CT
authors.lastname: Rao
authors.forename: Thennati
authors.initials: T
authors.lastname: Rajamannar
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012220:Rhinitis / Q000188:drug therapy
chemical_list: C528564:4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-ylbut-2-enyloxy)acetic acid; D000085:Acetates; D006634:Histamine H1 Antagonists; D010879:Piperazines; D010047:Ovalbumin