title: Pharmacology of a novel, orally active PDE4 inhibitor.
abstract: BACKGROUND
  Intracellular cyclic adenosine monophosphate (cAMP) in inflammatory cells and airway smooth muscle is critical to the modulation of inflammatory response generation. Phosphodiesterase 4 (PDE4), an enzyme that catalyzes cAMP degradation, is therefore being actively explored as a molecular target for the treatment of airway inflammation, particularly asthma and chronic obstructive pulmonary disease. The field has undergone major advances in optimizing generation of compounds with a safe therapeutic margin; however, most PDE4 inhibitors tested so far have unacceptable side effects, particularly nausea and vomiting.
  
  
  METHODS
  We evaluated NIS-62949 in a wide range of in vitro and ex vivo cell-based assays to ascertain its anti-inflammatory potential. The compound was evaluated in murine models of lipopolysaccharide-induced endotoxemia and pulmonary neutrophilia. Parameters of airway inflammation, airway hyperreactivity and bronchoconstriction were evaluated in a guinea pig model of antigen-induced allergy. In order to assess the emetic potential, the compound was evaluated biochemically for binding to high-affinity rolipram-binding site. Subsequently, the compound was tested in a surrogate model for emesis, and the results obtained were correlated directly to tests conducted in a Beagle dog model.
  
  
  RESULTS
  NIS-62949 is a potent, highly selective PDE4 inhibitor. The compound demonstrated potent ability to inhibit tumor necrosis factor-alpha release from human peripheral blood mononuclear cells, lymphocyte proliferation and cytokine production. The in vitro profile of NIS-62949 prompted further evaluation of the compound in vivo and the compound was found to be comparable to roflumilast in several experimental models of pulmonary inflammation. Importantly, NIS-62949 displayed a safer profile compared to roflumilast.
  
  
  CONCLUSIONS
  Our results report the development of a promising, novel PDE4 inhibitor, NIS-62949, with a wider therapeutic window as compared to second-generation PDE4 inhibitors such as roflumilast.
authors.affiliation: Department of Pharmacology, Ranbaxy Research Laboratories, Gurgaon, India.
authors.forename: Sunanda G
authors.initials: SG
authors.lastname: Dastidar
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Shirumalla
authors.forename: Deepa
authors.initials: D
authors.lastname: Rajagopal
authors.forename: Shiwani
authors.initials: S
authors.lastname: Chaudhary
authors.forename: Kamna
authors.initials: K
authors.lastname: Nanda
authors.forename: Pawan
authors.initials: P
authors.lastname: Sharma
authors.forename: Mahesh Kumar
authors.initials: MK
authors.lastname: Seth
authors.forename: Sarala
authors.initials: S
authors.lastname: Balachandran
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.forename: Venkata
authors.initials: V
authors.lastname: Palle