Search

• First disclosure of VU6005806/AZN-00016130, an M 4 PAM profiled as a putative candidate. • Novel SAR findings based on novel variations to the C3 position on the pyridazine core. • Minimum effective dose of 0.56 mg/kg po in rat AHL. This letter describes progress towards an M 4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3- c ]pyridazine core has been a consistent feature of key M 4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • First description of the SAR that led to the discovery of VU2957 (Valiglurax). • Valiglurax is only the second mGlu4 PAM clinical candidate for Parkinson's disease. • The new series afford improvements in protein binding, half-life in vivo , CNS penetration and oral bioavailability. • Highlights subtle differences in positioning of hydrogen-bond acceptors and impact on CNS penetration/P-gp liability. Abstract This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu 4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration). [ABSTRACT FROM AUTHOR]

Previous reports from our laboratory disclosed the structure and activity of a novel 1 H -pyrazolo[4,3- b ]pyridine-3-amine scaffold ( VU8506 ) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson’s disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu 4 PAMs, leading to 9i (hmGlu 4 EC 50  = 43 nM; AhR activation = 2.3-fold). [ABSTRACT FROM AUTHOR]

This letter describes the further chemical optimization of the picolinamide-derived family of mGlu 4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC 50 = 95 nM, 89% Glu Max) mGlu 4 PAM with an attractive DMPK profile (brain:plasma K p = 1.3), rat CL p = 4.0 mL/min/kg, t 1/2 = 3.7 h) and robust efficacy in our standard preclinical Parkinson’s disease model, haloperidol-induced catalepsy (HIC). [ABSTRACT FROM AUTHOR]

The synthesis and SAR of 4-methoxy-3-(piperidin-4-yl) benzamides identified after a high-throughput screen of the MLPCN library is reported. SAR was explored around the 3-piperidine substituent as well as the amide functionality of the reported compounds. Starting from the initial lead compounds, 1 – 7 , iterative medicinal chemistry efforts led to the identification of ML352 ( 10m ). ML352 represents a potent and selective inhibitor of CHT based on a drug-like scaffold. [ABSTRACT FROM AUTHOR]

Abstract: This Letter describes a novel series of GIRK activators identified through an HTS campaign. The HTS lead was a potent and efficacious dual GIRK1/2 and GIRK1/4 activator. Further chemical optimization through both iterative parallel synthesis and fragment library efforts identified dual GIRK1/2 and GIRK1/4 activators as well as the first examples of selective GIRK1/4 activators. Importantly, these compounds were inactive on GIRK2 and other non-GIRK1 containing GIRK channels, and SAR proved shallow. [Copyright &y& Elsevier]

Abstract: A structure–activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation. [Copyright &y& Elsevier]

Abstract: This Letter describes a chemical lead optimization campaign directed at a weak mGlu5 NAM discovered while developing SAR for the mGlu5 PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu5 NAMs, mGlu5 PAMs as well as mGlu5 partial antagonists. [Copyright &y& Elsevier]

Abstract: Herein we disclose the synthesis and SAR of a series of 4-(phenylsulfamoyl)phenylacetamide compounds as mGlu4 positive allosteric modulators (PAMs) that were identified via a functional HTS. An iterative parallel approach to these compounds culminated in the discovery of VU0364439 (11) which represents the most potent (19.8nM) mGlu4 PAM reported to date. [ABSTRACT FROM AUTHOR]

Abstract: The addition of 4equiv of phenyl ethynyl dimethyl alane (formed by treatment of phenyl acetylene with n-BuLi followed by Me2AlCl) to 2,3-epoxy geraniol results in the formation of the C-3 alkynyl addition product and the Yamamoto rearrangement/addition product, in 53 and 18% yield, respectively. Replacing the alane reagent with an aluminate (formed by treatment of phenyl acetylene with n-BuLi followed by Me3Al) and adding BF3·OEt2 result in formation of the C-3 addition product in 73% yield. [Copyright &y& Elsevier]

Abstract: Efforts toward the synthesis of the decalin ring system common to the hibarimicin shunt metabolite HMP-Y1 and parent aglycone hibarimicinone are reported herein. An intramolecular Diels–Alder cyclization rapidly generated the decalin framework. Two approaches toward completion of the AB decalin were vetted. Incorporation of a phenylsulfonyl leaving group β- to both a ketone and a γ-lactone followed by base-induced elimination of sulfinate led to the undesired α,β-unsaturated lactone. Methanolysis of the γ-lactone followed by elimination produced the unexpected bridged cyclic ether by way of an intramolecular oxy-Michael addition of the endo oriented C13 alcohol. [Copyright &y& Elsevier]

The activin-like kinases are a family of kinases that play important roles in a variety of disease states. Of this class of kinases, ALK2, has been shown by a gain-of-function to be the primary driver of the childhood skeletal disease fibrodysplasia ossificans progressiva (FOP) and more recently the pediatric cancer diffuse intrinsic pontine glioma (DIPG). Herein, we report our efforts to identify a novel imidazo[1,2- a pyridine scaffold as potent inhibitors of ALK2 with good in vivo pharmacokinetic properties suitable for future animal studies. [ABSTRACT FROM AUTHOR]

Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating the need to discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that mosquito inward rectifier potassium (Kir) channels represent viable molecular targets for developing insecticides with new mechanisms of action. Here we describe the discovery and characterization of VU041, a submicromolar-affinity inhibitor of Anopheles (An.) gambiae and Aedes (Ae.) aegypti Kir1 channels that incapacitates adult female mosquitoes from representative insecticide-susceptible and -resistant strains of An. gambiae (G3 and Akron, respectively) and Ae. aegypti (Liverpool and Puerto Rico, respectively) following topical application. VU041 is selective for mosquito Kir channels over several mammalian orthologs, with the exception of Kir2.1, and is not lethal to honey bees. Medicinal chemistry was used to develop an analog, termed VU730, which retains activity toward mosquito Kir1 but is not active against Kir2.1 or other mammalian Kir channels. Thus, VU041 and VU730 are promising chemical scaffolds for developing new classes of insecticides to combat insecticide-resistant mosquitoes and the transmission of mosquito-borne diseases, such as Zika virus, without harmful effects on humans and beneficial insects. [ABSTRACT FROM AUTHOR]

This letter describes progress towards an M 4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3- c ]pyridine core to an equipotent, non-CNS penetrant thieno[2,3- c ]pyrdin-7(6 H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M 4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats. [ABSTRACT FROM AUTHOR]

• First detailed SAR account around TREK1/2 activators. • First optimization campaign directed at BL-1249. • Discovery of new in vitro and in vivo tool compound, ONO-2960632/VU6011992. This letter describes a focused, multi-dimensional optimization campaign around BL-1249, a fenamate class non-steroidal anti-inflammatory and a known activator of the K 2P potassium channels TREK-1 (K 2P 2.1) and TREK-2 (K 2P 10.1). While BL-1249 has been widely profiled in vitro as a dual TREK-1/2 activator, poor physicochemical and DMPK properties have precluded a deeper understanding of the therapeutic potential of these key K 2P channels across a broad spectrum of peripheral and central human disease. Here, we report multi-dimensional SAR that led to a novel TREK-1/2 dual activator chemotype, exemplified by ONO-2960632/VU6011992, with improved DMPK properties, representing a new lead for further optimization towards robust in vivo tool compounds. [ABSTRACT FROM AUTHOR]

The prefrontal cortex (PFC) integrates information from multiple inputs to exert top-down control allowing for appropriate responses in a given context. In psychiatric disorders such as posttraumatic stress disorder, PFC hyperactivity is associated with inappropriate fear in safe situations. We previously reported a form of muscarinic acetylcholine receptor (mAChR)–dependent long-term depression in the PFC that we hypothesize is involved in appropriate fear responding and could serve to reduce cortical hyperactivity following stress. However, it is unknown whether this long-term depression occurs at fear-related inputs. Using optogenetics with extracellular and whole-cell electrophysiology, we assessed the effect of mAChR activation on the synaptic strength of specific PFC inputs. We used selective pharmacological tools to assess the involvement of M 1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. M 1 mAChR activation induced long-term depression at inputs from the ventral hippocampus and basolateral amygdala but not from the mediodorsal nucleus of the thalamus. We found that systemic M 1 mAChR antagonism impaired contextual fear extinction. Treatment with an M 1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning–conditioned mice. M 1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M 1 mAChR function is required for proper contextual fear extinction. Furthermore, an M 1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M 1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel series of selective and CNS penetrant mGlu 7 NAMs. • Identified a 1,3,4-oxadiazole as biosiostere for a labile amide linker. • Iterative libraries quickly optimized this novel tricyclic series. Abstract This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu 7 negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu 7 NAM chemotype led to the discovery of VU6019278, a potent mGlu 7 NAM (IC 50 = 501 nM, 6.3% L-AP 4 Min) with favorable plasma protein binding (rat f u = 0.10), low predicted hepatic clearance (rat CL hep = 27.7 mL/min/kg) and high CNS penetration (rat K p = 4.9, K p,uu = 0.65). [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • First description of the role of the β-aminocarboxamide moiety within M 4 PAM scaffolds. • Novel des -amino and tricyclic variant M 4 PAMs. • The role of the IMHB motif was established, and could be re-enforced by tricycles. Abstract This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M 4 PAMs and question if the NH 2 group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the β-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH 2 , generating des -amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M 4 PAMs with poor DMPK properties. Cyclization of the β-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M 4 PAMs, many as potent as the classical bicyclic β-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the β-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M 4 PAM activity within classical bicyclic M 4 PAM scaffolds. [ABSTRACT FROM AUTHOR]

This letter describes the chemical optimization of a new series of M 1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 ( 7 ), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties). [ABSTRACT FROM AUTHOR]

Herein we describe the continued optimization of M 4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3- c ]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology. [ABSTRACT FROM AUTHOR]

This Letter details the discovery and subsequent optimization of a novel M 4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M 4 PAM chemotypes. Optimized compounds in this series demonstrated improved M 4 PAM potency on both human and rat M 4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma K p = 5.3, K p,uu = 2.4; MDCK-MDR1 (P-gp) ER = 1.1). [ABSTRACT FROM AUTHOR]

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M 4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M 4 (hM 4 IC 50 s < 200 nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma K p = 2.1, K p,uu = 1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M 1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists. [ABSTRACT FROM AUTHOR]

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M 4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M 4 (IC 50 s < 300 nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K p,uu = 0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL p = 5.37 mL/min/kg). Surprisingly, this series displayed pan -muscarinic antagonist activity across M 1–5 , despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan -muscarinic antagonist agents. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This letter describes the chemical optimization of a novel series of M 4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3- c ]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 ( 5 ). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration). [ABSTRACT FROM AUTHOR]

This Letter describes the chemical optimization of a novel series of M 4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M 4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M 4 PAM activity. [ABSTRACT FROM AUTHOR]

This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M 4 PAM activity in most M 4 PAMs to date, within the thieno[2,3- b ]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M 4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core. [ABSTRACT FROM AUTHOR]

Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu7 is expressed presynaptically at the Schaffer collateral (SC)-CA1 synapse in the hippocampus in adult animals. Coupled with the inhibitory effects of Group III mGlu receptor agonists on transmission at this synapse, mGlu7 is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu7-selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu7-negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu7 in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu7 agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu7 by stimulation of SC-CA1 afferents. However, LSP4-2022 also reduced evoked monosynaptic IPSCs in CA1 pyramidal cells and, in contrast to its effect on SC-CA1 EPSPs, ADX71743 reversed the ability of high-frequency stimulation of SC afferents to reduce IPSC amplitudes. Furthermore, blockade of mGlu7 prevented induction of LTP at the SC-CA1 synapse and activation of mGlu7 potentiated submaximal LTP. Together, these data suggest that mGlu7 serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu7 by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu7-mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu7 could serve as a novel therapeutic target for treatment of cognitive disorders. [ABSTRACT FROM AUTHOR]

Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence of insecticide-resistant mosquito populations is reducing the effectiveness of conventional insecticides and threatening current vector control strategies, which has created an urgent need to identify new molecular targets against which novel classes of insecticides can be developed. We previously demonstrated that small molecule inhibitors of mammalian Kir channels represent promising chemicals for new mosquitocide development. In this study, high-throughput screening of approximately 30,000 chemically diverse small-molecules was employed to discover potent and selective inhibitors of Aedes aegypti Kir1 (AeKir1) channels heterologously expressed in HEK293 cells. Of 283 confirmed screening ‘hits’, the small-molecule inhibitor VU625 was selected for lead optimization and in vivo studies based on its potency and selectivity toward AeKir1, and tractability for medicinal chemistry. In patch clamp electrophysiology experiments of HEK293 cells, VU625 inhibits AeKir1 with an IC50 value of 96.8 nM, making VU625 the most potent inhibitor of AeKir1 described to date. Furthermore, electrophysiology experiments in Xenopus oocytes revealed that VU625 is a weak inhibitor of AeKir2B. Surprisingly, injection of VU625 failed to elicit significant effects on mosquito behavior, urine excretion, or survival. However, when co-injected with probenecid, VU625 inhibited the excretory capacity of mosquitoes and was toxic, suggesting that the compound is a substrate of organic anion and/or ATP-binding cassette (ABC) transporters. The dose-toxicity relationship of VU625 (when co-injected with probenecid) is biphasic, which is consistent with the molecule inhibiting both AeKir1 and AeKir2B with different potencies. This study demonstrates proof-of-concept that potent and highly selective inhibitors of mosquito Kir channels can be developed using conventional drug discovery approaches. Furthermore, it reinforces the notion that the physical and chemical properties that determine a compound's bioavailability in vivo will be critical in determining the efficacy of Kir channel inhibitors as insecticides. [ABSTRACT FROM AUTHOR]

[Display omitted] In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR 4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M 4 potency, and further structure–activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M 4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration. [ABSTRACT FROM AUTHOR]

[Display omitted] This Letter details our efforts to develop novel tricyclic M 4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3- b ]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3- b :5,4-c′]dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M 4 receptor. [ABSTRACT FROM AUTHOR]

The human Ether-à-go-go-related gene (hERG)-encoded K+ current, IKr is essential for cardiac repolarization but is also a source of cardiotoxicity because unintendedhERGinhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes IKr block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC70 of dofetilide, a well characterized hERG blocker. One compound, VU0405601, with the desired activity was further characterized. In isolated, Langendorff-perfused rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretreatment with VU0405601. Patch clamp analysis in stable hERG-HEK cells showed effects on current amplitude, inactivation, and deactivation. VU0405601 increased the IC50 of dofetilide from 38.7 to 76.3 nM. VU0405601 mitigates the effects of hERG blockers from the extracellular aspect primarily by reducing inactivation, whereas most clinically relevant hERG inhibitors act at an inner pore site. Structure-activity relationships surrounding VU0405601 identified a 3-pyridiyl and a naphthyridine ring system as key structural components important for preventing hERG inhibition by multiple inhibitors. These findings indicate that small molecules can be designed to reduce the sensitivity of hERG to inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: 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 =260nM). 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. [Copyright &y& Elsevier]

[Display omitted] 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-5 H -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. [ABSTRACT FROM AUTHOR]

• Discovery of novel 2,3-dimethylimidazo[1,2- a ]pyrazine-6-carboxamide-based M 4 PAMs. • Broad survey of diverse heterocyclic cores. • Balanced human and rat M 4 PAM potency with excellent CNS penetration. This Letter details our efforts to develop new M 4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2 H -indazole-5-carboxamide core or a 1-methyl-1 H -benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4- h ]quinazoline core and an 1-methyl-1 H -[1,2,3]triazolo[4,5- h ]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M 4. [ABSTRACT FROM AUTHOR]

• Discovery of two novel tricyclic-based M 4 PAMs. • Utility of scaffold hopping to improve potency/properties/DMPK. • Balanced human and rat M 4 PAM potency. • Rare 8,9-dimethyl-8 H -pyrazolo[3,4- h ]quinazoline and 1-methyl-1 H -[1,2,3]triazolo[4,5- h ]quinazoline cores. This Letter details our efforts to discover structurally unique M 4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1 H -benzo[ d ][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo[1,2- a ]pyrazine-6-carboxamide core that provided improved M 4 PAM activity and CNS penetration. [ABSTRACT FROM AUTHOR]

• Novel 2.4-dimehtylcinnoline-based M 4 PAMs. • Utility of scaffold hopping to improve properties/DMPK. • Balanced human and rat M 4 PAM potency. This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M 4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M 4 PAM activity and improved clearance and protein binding profiles. [ABSTRACT FROM AUTHOR]