US EPA

582127 

Journal Article 

Selective naphthalene H3 receptor inverse agonists with reduced potential to induce phospholipidosis and their quinoline analogs 

Rodriguez Sarmiento, RM; Nettekoven, MH; Taylor, S; Plancher, JM; Richter, H; Roche, O 

2009 

Yes 

Bioorganic & Medicinal Chemistry Letters
ISSN: 0960-894X
EISSN: 1464-3405 

19 

15 

4495-4500 

English 

19524437 

10.1016/j.bmcl.2009.03.100 

We reported earlier the refinement of our initial five-point pharmacophore model for the Histamine 3 receptor (H3R), 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 H3R 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 H3 receptor, their selectivity against H1R, H2R and H4R, 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 H3R pharmacophore model to lead us towards the quinoline series. This series is perceived to have intrinsic advantages with respect to its amphiphilic vector. 

Histamine H3 receptor; SAR; Pharmacophore model; Naphthalene; Phospholipidosis; Amphiphilic vector; Amphiphilicity; Quinoline