Bradford C. Van Wagenen

NPS 1506, A Novel NMDA Receptor Antagonist and Neuroprotectant: Review of Preclinical and Clinical Studies

ABSTRACT: NPS 1506 is a moderate affinity, uncompetitive N‐methyl‐d‐aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2‐hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1–1.0 mg/kg, with peak plasma concentrations ranging from 8–80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK‐801‐like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization.

Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues.

Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.

Chiral synthesis and pharmacological evaluation of NPS 1407 : A potent, stereoselective NMDA receptor antagonist

The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual stereoisomers. The S isomer (4a) was found to be 12 times more potent than the R isomer (4b). Compound 4a demonstrated in vivo pharmacological activity in neuroprotection and anticonvulsant assays.

Modulation of Group III Metabotropic Glutamate Receptors by Hydrogen Ions

Protons act as neuromodulators and produce significant effects on synaptic transmission. The molecular basis of neuromodulation by extracellular protons is partially explained by their effects on certain neurotransmitter receptors and ion channels. The metabotropic glutamate receptors (mGluRs) are a family of eight receptor subtypes that are widely expressed throughout the mammalian CNS. In this study, the effects of physiologically relevant changes in extracellular pH were examined in mammalian cells expressing the mGluR subtypes: human mGluR1a, mGluR4a, mGluR5d or mGluR8b. The signal transduction coupling properties of mGluR4a and mGluR8b were switched from the adenylate cyclase (Gi) pathway to the phospholipase C (Gq) pathway by coexpression of a promiscuous G protein. Fluorometric imaging plate reader was used to measure changes in cytoplasmic calcium concentrations in response to agonist. Extracellular acidification from pH 8.0 to pH 6.5 progressively diminished mGluR4 responsiveness to the agonists L-glutamate and (2S,1′S,2′R)-2-(carboxycyclopropyl)glycine (L-CCG-I), and this inhibition was characterized by insurmountable antagonism. By comparison, extracellular acidification did not significantly alter mGluR8 responses to agonists. Furthermore, agonist activation of mGluR1a and mGluR5d was virtually unaffected by changes in pH. Because mGluR4 is expressed presynaptically and its activation inhibits the release of neurotransmitters such as glutamate and GABA, we propose that the net effect of proton inhibition of mGluR4 would be to reverse or prevent that suppression of neurotransmitter release. As such, local decreases in pH could have significant effects on the regulation of transmitter release and synaptic tone via modulation of mGluR4.

Synthesis, biological activity, and absolute stereochemical assignment of NPS 1392 : A potent and stereoselective NMDA receptor antagonist

The synthesis, biological activity, and single crystal X-ray structure of NPS 1392, (R)-(-)-3,3-bis(3-fluorophenyl)-2-methylpropan-1-amine (3a), a potent, stereoselective antagonist of the NMDA receptor, are described. The NMDA receptor selectively bound the levo isomer (3a) over its enantiomer (3b), which prompted a rigorous absolute configuration assignment. NPS 1392 has the R configuration based on the single-crystal X-ray diffraction analysis of the hydroiodide salt of NPS 1392. This compound is a potential neuroprotective agent for use in the treatment of ischemic stroke.

Discovery and Development of Calcimimetic and Calcilytic Compounds

The extracellular calcium receptor (CaR) is a G protein-coupled receptor (GPCR) and the pivotal molecule regulating systemic Ca2+ homeostasis. The CaR was a challenging target for drug discovery because its physiological ligand is an inorganic ion (Ca2+) rather than a molecule so there was no structural template to guide medicinal chemistry. Nonetheless, small molecules targeting this receptor were discovered. Calcimimetics are agonists or positive allosteric modulators of the CaR, while calcilytics are antagonists and all to date are negative allosteric modulators. The calcimimetic cinacalcet was the first allosteric modulator of a GPCR to achieve regulatory approval and is a first-in-class treatment for secondary hyperparathyroidism in patients on dialysis, and for hypercalcemia in some forms of primary hyperparathyroidism. It is also useful in treating some rare genetic diseases that cause hypercalcemia. Two other calcimimetics are now on the market (etelcalcetide) or under regulatory review (evocalcet). Calcilytics stimulate the secretion of parathyroid hormone and were initially developed as treatments for osteoporosis. Three different calcilytics of two different chemotypes failed in clinical trials due to lack of efficacy. Calcilytics are now being repurposed and might be useful in treating hypoparathyroidism and several rare genetic diseases causing hypocalcemia. The challenges ahead for medicinal chemists are to design compounds that select conformations of the CaR that preferentially target a particular signalling pathway and/or that affect the CaR in a tissue-selective manner.