title: Selective naphthalene H(3) receptor inverse agonists with reduced potential to induce phospholipidosis and their quinoline analogs.
abstract: We reported earlier the refinement of our initial five-point pharmacophore model for the Histamine 3 receptor (H(3)R), with a new acceptor feature important for binding and selectivity against the other histamine receptor subtypes 1, 2 and 4. This approach was validated with a new series of H(3)R inverse agonists: the naphthalene series. In this Letter, we describe our efforts to overcome the phospholipidosis flag identified with our initial lead compound (1a). During the optimization process, we monitored the potency of our molecules toward the H(3) receptor, their selectivity against H(1)R, H(2)R and H(4)R, as well as some key molecular properties that may influence phospholipidosis. Encouraged by the promising profile of the naphthalene series, we used our deeper understanding of the H(3)R pharmacophore model to lead us towards the quinoline series. This series is perceived to have intrinsic advantages with respect to its amphiphilic vector.
authors.affiliation: Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. rosa.maria_rodriguez_sarmiento@roche.com
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Rodríguez Sarmiento
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Nettekoven
authors.forename: Sven
authors.initials: S
authors.lastname: Taylor
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Plancher
authors.forename: Hans
authors.initials: H
authors.lastname: Richter
authors.forename: Olivier
authors.initials: O
authors.lastname: Roche
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D017442:Histamine Agonists / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry*; D011485:Protein Binding; D011804:Quinolines / Q000737:chemistry*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D017442:Histamine Agonists; D009281:Naphthalenes; D010743:Phospholipids; D011804:Quinolines; D018100:Receptors, Histamine H3; C031721:naphthalene