H3R inverse agonists was designed by feasible pharmacophore model. It is interesting that rat microsomal clearance is negatively correlated with pKa, and hERG correlation model is relying solely on two descriptors, the percentage of membrane-bound compound in PAMPA, and log D.
Drug design focused on downsizing the molecular weight of macrocyclic peptide GM-109. Dipeptide analogues of Phe-Thy(tBu) as essential pharmacophore was synthesized, and then orally available dipeptide antagonists were discovered.
This report is about an analysis of the interrelation of physicochemical properties and the human renal clearance for a data set of 391 drugs or compounds tested n humans.
The lipophilic efficiency is defined by pIC50 (potency) - clogP (lipophilicity), so that this descriptor is a good reference index of druglikeness. This paper reported that analysis of the lipophilic efficiency of parallel synthesized compounds provided new insight for the design of potent, metabolically stable CB2 agonists.
MK-0533 was Merck's clinical candidate (Phase-II, but now discontinued) of SPARM. The indole scaffold was probably originated from their traditional drug of indomethacin as a NSAID. SAR was featured by Fig. 1. The drug design was N-shuffle of indole to prevent deasylation. MK-0533 showed good in vivo efficacy and reduced side-effects at animal models.
More recently, they published a SPARM with weak alpha-PPAR activity.