This Letter describes the synthesis and structure-activity-relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of alternative halogenated piperidinyl benzimidazolone privileged structures, in combination with a key ( S)-methyl group, novel PLD inhibitors with low nM potency and unprecedented levels of PLD1 isoform selectivity (similar to 1700-fold) over PLD2 were developed. (C) 2009 Elsevier Ltd. All rights reserved.

This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M-1 (mAChR M-1). Through the continued optimization of M-1 PAM tool compound VU0453595, with a focus on replacement of the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one with a wide variety of alternative 4,5-dihydropyrrolo-fused heteroaromatics, the generation of M-1 PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M-1 mAChR, and no M-1 agonism. Both compounds have favorable preliminary PK profiles in vitro; 8b additionally demonstrates high brain exposure in a rodent IV cassette model.

Hypoxia and ischemia are linked to several serious public health problems that affect most major organ systems. Specific examples include diseases of the cardiovascular, pulmonary, renal, neurologic, and musculoskeletal systems. The most significant pathway for cellular response to hypoxia is the hypoxia inducible factor (HIF) pathway. HIFs are transcription factors responsible for the activation of genes which encode proteins that mediate adaptive responses to reduced oxygen availability. A high-throughput cell-based HIF-mediated gene reporter screen was carried out using the NIH's Molecular Libraries Small Molecule Repository to identify activators of the HIF pathway. This communication describes the subsequent medicinal chemistry optimization of a triazine scaffold that led to the identification of the new molecular probe ML228. A discussion of HIF activation SAR within this chemotype as well as detailed in vitro characterization of the probe molecule is presented here. (C) 2011 Elsevier Ltd. All rights reserved.

A high-throughput screen utilizing a depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the MLSMR collection of over 300,000 compounds. An iterative medicinal chemistry approach was initiated and from this effort, ML277 was identified as a potent activator of KCNQ1 channels (EC50 = 260 nM). ML277 was shown to be highly selective against other KCNQ channels (> 100-fold selectivity versus KCNQ2 and KCNQ4) as well as against the distantly related hERG potassium channel. (C) 2012 Elsevier Ltd. All rights reserved.

This letter describes the further chemical optimization of the 5-amino-thieno(2,3-c]pyridazine series (VU0467154/VU0467485) of M-4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties. (C) 2017 Elsevier Ltd. All rights reserved.

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.