Frank Lovering

Escape from flatland: increasing saturation as an approach to improving clinical success.

The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp(3) (Fsp(3)) where Fsp(3) = (number of sp(3) hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. We demonstrate that both complexity (as measured by Fsp(3)) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations, we further demonstrate that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting.

Conformationally restricted inhibitors of the high affinity L-glutamate transporter

Abstract A series of acidic amino acids has been prepared and evaluated in an effort to identify the structural features required for binding to and inhibiting the high affinity uptake system that clears L-glutamate from the synaptic cleft during excitatory amino acid-mediated neurotransmission in the mammalian CNS.

A conformationally constrained competitive inhibitor of the sodium-dependent glutamate transporter in forebrain synaptosomes: l-anti-endo-3,4-methanopyrrolidine dicarboxylate ☆

A series of L-3,4-methanopyrrolidine dicarboxylate isomers were investigated as potential inhibitors of the high affinity, sodium-dependent glutamate transporter in rat forebrain synaptosomes. Of the isomers tested, only L-anti-endo-3,4-methanopyrrolidine dicarboxylate (L-anti-endo-MPDC) blocked the uptake of [3H]D-aspartate, a non-metabolized substrate. Kinetic analysis demonstrated that L-anti-endo-MPDC is a potent competitive inhibitor (Ki = 5 microM) comparable to that of L-glutamate and L-trans-2,4-pyrrolidine dicarboxylate (L-trans-2,4-PDC). Conformational analysis of L-glutamate, L-trans-2,4-PDC and L-anti-endo-MPDC are used to refine the pharmacophore model of the transporter binding site.

Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)

A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity.