Herein, we report the synthesis and structure-activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl)oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1 mu M against D-1, D-2L, D-2S, D-3, and D-5). (C) 2016 Elsevier Ltd. All rights reserved.

This Letter describes the continued chemical optimization of the VU0453595 series of M-1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihy-dro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M-1 PAM potency, but significantly improved CNS distribution (K(p)s 0.3-3.1). Moreover, this campaign provided fundamentally distinct M-1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors. (C) 2016 Elsevier Ltd. All rights reserved.

Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M-4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M-1/M-4-preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M-4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile. (c) 2015 Elsevier Ltd. All rights reserved.

This Letter describes the further lead optimization of the VU0486321 series of mGlu(1) positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu(1) PAM potency, DMPK profile, CNS penetration and mGluR selectivity. (C) 2016 Elsevier Ltd. All rights reserved.

Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu(1) and mGlu(5)) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu(1/5) NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1',2': 1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents. (C) 2016 Elsevier Ltd. All rights reserved.

This letter describes the re-exploration of the mGlu(1) PAM Ro 07-11401 scaffold through a multi-dimensional, iterative parallel synthesis approach. Unlike recent series of mGlu(1) PAMs with robust SAR, the SAR around the Ro 07-11401 structure was incredibly steep (only similar to 6 of 200 analogs displayed mGlu1 PAM activity), and reminiscent of the CPPHA mGlu(5) PAM scaffold. Despite the steep SAR, two new thiazole derivatives were discovered with improved in vitro DMPK profiles and similar to 3- to 4-fold improvement in CNS exposure (K(p)s 1.01-1.19); albeit, with a similar to 3-fold diminution in mGlu1 PAM potency, yet comparable efficacy (similar to 5-fold leftward shift of the glutamate concentration-response curve at 10 mu M). Thus, this effort has provided additional CNS penetrant mGlu(1) PAM tools in a different chemotype than the VU0486321 scaffold. These compounds will permit a better understanding of the pharmacology and therapeutic potential of selective mGlu(1) activation, while highlighting the steep SAR challenges that can often be encountered in GPCR allosteric modulator discovery. (C) 2016 Elsevier Ltd. All rights reserved.