Discovery of 3-Substituted Aminocyclopentanes as Potent and Orally Bioavailable NR2B Subtype-Selective NMDA Antagonists

Abstract

A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.

Unprecedented Therapeutic Potential with a Combination of A2A/NR2B Receptor Antagonists as Observed in the 6-OHDA Lesioned Rat Model of Parkinson's Disease

“…Preladenant was reported to be devoid of in-vitro risks of drug interactions with cytochrome P-450 (CYP) and P-glycoprotein (Pgp) substrates, a finding confirmed in clinical studies [62] . Absence of in-vitro interactions with CYPs and Pgp was also reported for the NR2B antagonist Merck 22 compound [49] . Finally, in human subjects, Istradefylline does not impair CYP3A-mediated drug metabolism, its effects being restricted to modest inhibition of P-gp [63] .…”

“…All compounds were obtained from commercially available standard suppliers with the exception of compound ‘Merck 22’, which was synthesized based on methodology described by [49] . The A 2A antagonists were Sch-58261 (Synthelabo), Preladenant (Endotherm), Tozadenant (Pharmablock) and Istradefylline (Diverchim).…”

A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists

“…EVT-101 [5-(3-(difluoromethyl)-4-fluorophenyl)-3-((2-methyl-1H-imidazol-1-yl)methyl)pyridazine] and MK-22 [ N -[(1S,3S)-3-[3-(4-methylbenzyl)-1,2,4-oxadiazol-5-yl]cyclopentyl]-1H-pyrazolo[3,4-day]pyrimidin-4-amine] were synthesized in-house at Pfizer (Groton, CT) following the procedure described in Kemp and Tasker (2009) and Layton et al (2011) , respectively. EVT-101 is achiral (i.e., possessing no stereocenters), whereas MK-22 is a pure enantiomer, being synthesized from chiral starting material.…”

“…Many, such as CP-101,606 (Traxoprodil; Chenard et al, 1995 ), Ro25-6981 ( Fischer et al, 1997 ), or besonprodil ( Chizh et al, 2001 ), share the same phenylethanolamine scaffold as ifenprodil. Others, including a number of highly potent and orally active GluN2B antagonists such as EVT-101 ( Kemp and Tasker, 2009 ) and to a lesser extent MK-22 ( Layton et al, 2011 ), bear strikingly different structural motifs, thus questioning whether these compounds adopt a similar binding mode to ifenprodil. Crystal structures recently established the existence of a "phenylethanolamine binding site" at a dimer interface between GluN1 and GluN2B NTDs ( Karakas et al, 2011 ; Karakas and Furukawa, 2014 ; Lee et al, 2014 ).…”

Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder

“…BMS-986169 showed negligible activity in a broad assay panel consisting of 40 additional targets. Importantly, BMS-986169 weakly inhibited hERG channels (IC 50 5 28.4 mM), an off-target liability that has been challenging to address in chemical scaffolds targeting the GluN2B NAM site (Brown et al, 2011;Layton et al, 2011;Müller et al, 2011).…”