Selective naphthalene H(3) receptor inverse agonists with reduced potential to induce phospholipidosis and their quinoline analogs.
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.
Rodríguez Sarmiento
Rosa María
RM
Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. rosa.maria_rodriguez_sarmiento@roche.com
Nettekoven
Matthias H
MH
Taylor
Sven
S
Plancher
Jean-Marc
JM
Richter
Hans
H
Roche
Olivier
O
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
D017442:Histamine Agonists; D009281:Naphthalenes; D010743:Phospholipids; D011804:Quinolines; D018100:Receptors, Histamine H3; C031721:naphthalene