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1.
Thomas M. Bridges J. Phillip Kennedy Hyekyung P. Cho Micah L. Breininger Patrick R. Gentry Corey R. Hopkins P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(2):558-562
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative library synthesis approach delivered the first selective M5 PAM (no activity at M1–M4 @ 30 μM), and an important tool compound to study the role of M5 in the CNS. 相似文献
2.
Thomas M. Bridges J. Phillip Kennedy Meredith J. Noetzel Micah L. Breininger Patrick R. Gentry P.J. Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(6):1972-1975
This Letter describes a chemical lead optimization campaign directed at VU0119498, a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) with the goal of developing a selective M1 PAM. An iterative library synthesis approach delivered a potent (M1 EC50 = 830 nM) and highly selective M1 PAM (>30 μM vs M2–M5). 相似文献
3.
Reid PR Bridges TM Sheffler DJ Cho HP Lewis LM Days E Daniels JS Jones CK Niswender CM Weaver CD Conn PJ Lindsley CW Wood MR 《Bioorganic & medicinal chemistry letters》2011,21(9):2697-2701
This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M1 PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M1 PAM with an in vitro profile comparable to the prototypical M1 PAM, BQCA, but with an improved brain to plasma ratio. 相似文献
4.
Michael R. Wood Meredith J. Noetzel Michael S. Poslusney Bruce J. Melancon James C. Tarr Atin Lamsal Sichen Chang Vincent B. Luscombe Rebecca L. Weiner Hyekyung P. Cho Michael Bubser Carrie K. Jones Colleen M. Niswender Michael W. Wood Darren W. Engers Nicholas J. Brandon Mark E. Duggan P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(2):171-175
This letter describes the chemical optimization of a novel series of M4 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). 相似文献
5.
Darren W. Engers Bruce J. Melancon Allison R. Gregro Jeanette L. Bertron Sean R. Bollinger Andrew S. Felts Leah C. Konkol Michael R. Wood Katrina A. Bollinger Vincent B. Luscombe Alice L. Rodriguez Carrie K. Jones Michael Bubser Samantha E. Yohn Michael W. Wood Nicholas J. Brandon Mark E. Dugan Colleen M. Niswender Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2019,29(14):1714-1718
This letter describes progress towards an M4 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 M4 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. 相似文献
6.
Patrick R. Gentry Thomas M. Bridges Atin Lamsal Paige N. Vinson Emery Smith Peter Chase Peter S. Hodder Julie L. Engers Colleen M. Niswender J. Scott Daniels P. Jeffrey Conn Michael R. Wood Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2013,23(10):2996-3000
This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10 μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409 nM and 500 nM, respectively) with excellent mAChR selectivity (M1–M4 EC50s >30 μM) and a robust 20-fold leftward shift of the ACh CRC. 相似文献
7.
《Bioorganic & medicinal chemistry》2020,28(13):115531
The M3 muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure-activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M3 mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M3 mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M1, M2, and M4 mAChRs, and moderate selectivity over the M5 mAChR, indicating that compound 9 is an M3-preferring M3/M5 dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M3 mAChR for further investigation of its pharmacological function both in vitro and in vivo. 相似文献
8.
Bruce J. Melancon Michael R. Wood Meredith J. Noetzel Kellie D. Nance Eileen M. Engelberg Changho Han Atin Lamsal Sichen Chang Hyekyung P. Cho Frank W. Byers Michael Bubser Carrie K. Jones Colleen M. Niswender Michael W. Wood Darren W. Engers Dedong Wu Nicholas J. Brandon Mark E. Duggan Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(11):2296-2301
This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 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. 相似文献
9.
Michael S. Poslusney Christian Sevel Thomas J. Utley Thomas M. Bridges Ryan D. Morrison Nathan R. Kett Douglas J. Sheffler Colleen M. Niswender J.S. Daniels P.J. Conn Craig W. Lindsley Michael R. Wood 《Bioorganic & medicinal chemistry letters》2012,22(22):6923-6928
Utilizing a combination of high-throughput and multi-step synthesis, SAR in a novel series of M1 acetylcholine receptor antagonists was rapidly established. The efforts led to the discovery the highly potent M1 antagonists 6 (VU0431263), and 8f (VU0433670). Functional Schild analysis and radioligand displacement experiments demonstrated the competitive, orthosteric binding of these compounds; human selectivity data are presented. 相似文献
10.
Blake R. Bewley Paul K. Spearing Rebecca L. Weiner Vincent B. Luscombe Xiaoyan Zhan Sichen Chang Hyekyung P. Cho Alice L. Rodriguez Colleen M. Niswender P. Jeffrey Conn Thomas M. Bridges Darren W. Engers Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(18):4274-4279
This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp = 5.3, Kp,uu = 2.4; MDCK-MDR1 (P-gp) ER = 1.1). 相似文献
11.
Douglas J. Sheffler Christian Sevel Uyen Le Kimberly M. Lovell James C. Tarr Sheridan J.S. Carrington Hyekyung P. Cho Gregory J. Digby Colleen M. Niswender P. Jeffrey Conn Corey R. Hopkins Michael R. Wood Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2013,23(1):223-227
This letter describes the further exploration of two series of M1 allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M1 allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M1 allosteric agonist family (VU0357017) identified similar, subtle ‘molecular switches’ that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M1 activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism. 相似文献
12.
Kevin M. McGowan Kellie D. Nance Hykeyung P. Cho Thomas M. Bridges P. Jeffrey Conn Carrie K. Jones Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(6):1356-1359
This letter describes the continued optimization of M5 NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375 has an excessively long elimination half-life in rat (t1/2 = 80 h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M5 NAM of comparable potency to ML375, but with a rat t1/2 of less than 4 h. Steep SAR plagued this chemotype, and here we detail aniline replacements that offered some improvements over ML375, but failed to advance. Ultimately, incorporation of a single methyl group to the 9b-phenyl ring acted as a metabolic shunt, providing (S)-11 (VU6008667), an equipotent M5 NAM, with high CNS penetration, excellent selectivity versus M1–4 and the desired short half-life (t1/2 = 2.3 h) in rat. 相似文献
13.
Darren W. Engers Patrick R. Gentry Richard Williams Julie D. Bolinger C. David Weaver Usha N. Menon P. Jeffrey Conn Craig W. Lindsley Colleen M. Niswender Corey R. Hopkins 《Bioorganic & medicinal chemistry letters》2010,20(17):5175-5178
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 (19.8 nM) mGlu4 PAM reported to date. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2019,29(21):126678
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 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 M4 PAM activity and improved clearance and protein binding profiles. 相似文献
15.
《Bioorganic & medicinal chemistry letters》2014,24(15):3307-3314
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and other anxiolytics, produced dose proportional effects. 相似文献
16.
Andrew S. Felts Alice L. Rodriguez Ryan D. Morrison Daryl F. Venable Jason T. Manka Brittney S. Bates Anna L. Blobaum Frank W. Byers J. Scott Daniels Colleen M. Niswender Carrie K. Jones P. Jeffrey Conn Craig W. Lindsley Kyle A. Emmitte 《Bioorganic & medicinal chemistry letters》2013,23(21):5779-5785
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics. 相似文献
17.
James C. Tarr Michael R. Wood Meredith J. Noetzel Jeanette L. Bertron Rebecca L. Weiner Alice L. Rodriguez Atin Lamsal Frank W. Byers Sichen Chang Hyekyung P. Cho Carrie K. Jones Colleen M. Niswender Michael W. Wood Nicholas J. Brandon Mark E. Duggan P. Jeffrey Conn Thomas M. Bridges Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(13):2990-2995
This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3 mg/kg. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(15):3641-3646
We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE = 0.52, LELP = 3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series. 相似文献
19.
Madeline F. Long Julie L. Engers Sichen Chang Xiaoyan Zhan Rebecca L. Weiner Vincent B. Luscombe Alice L. Rodriguez Hyekyung P. Cho Colleen M. Niswender Thomas M. Bridges P. Jeffrey Conn Darren W. Engers Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(22):4999-5001
This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M4 PAM activity in most M4 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 M4 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. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2020,30(3):126812
This Letter details our efforts to discover structurally unique M4 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-1H-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 M4 PAM activity and CNS penetration. 相似文献