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1.
《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
2.
Michael S. Poslusney James M. Salovich Michael R. Wood Bruce J. Melancon Katrina A. Bollinger Vincent B. Luscombe Alice L. Rodriguez Darren W. Engers Thomas M. Bridges Colleen M. Niswender P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2019,29(3):362-366
This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M4 PAMs and question if the NH2 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 NH2, generating des-amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M4 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) M4 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 M4 PAM activity within classical bicyclic M4 PAM scaffolds. 相似文献
3.
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
4.
《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
5.
SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel,CNS penetrant tricyclic M4 PAMs
Trevor C. Chopko Changho Han Alison R. Gregro Darren W. Engers Andrew S. Felts Mike S. Poslusney Katrina A. Bollinger Ryan D. Morrison Michael Bubser Atin Lamsal Vincent B. Luscombe Hyekyung P. Cho Nathalie C. Schnetz-Boutaud Alice L. Rodriguez Sichen Chang J. Scott Daniels Donald F. Stec Colleen M. Niswender Bruce J. Melancon 《Bioorganic & medicinal chemistry letters》2019,29(16):2224-2228
This letter describes progress towards an M4 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(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats. 相似文献
6.
《Bioorganic & medicinal chemistry letters》2020,30(4):126811
This Letter details our efforts to develop new M4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-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-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M4. 相似文献
7.
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
8.
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
9.
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
10.
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
11.
Alaa Abdul-Ridha J. Robert Lane Shailesh N. Mistry Laura López Patrick M. Sexton Peter J. Scammells Arthur Christopoulos Meritxell Canals 《The Journal of biological chemistry》2014,289(48):33701-33711
Benzylquinolone carboxylic acid (BQCA) is the first highly selective positive allosteric modulator (PAM) for the M1 muscarinic acetylcholine receptor (mAChR), but it possesses low affinity for the allosteric site on the receptor. More recent drug discovery efforts identified 3-((1S,2S)-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one (referred to herein as benzoquinazolinone 12) as a more potent M1 mAChR PAM with a structural ancestry originating from BQCA and related compounds. In the current study, we optimized the synthesis of and fully characterized the pharmacology of benzoquinazolinone 12, finding that its improved potency derived from a 50-fold increase in allosteric site affinity as compared with BQCA, while retaining a similar level of positive cooperativity with acetylcholine. We then utilized site-directed mutagenesis and molecular modeling to validate the allosteric binding pocket we previously described for BQCA as a shared site for benzoquinazolinone 12 and provide a molecular basis for its improved activity at the M1 mAChR. This includes a key role for hydrophobic and polar interactions with residues Tyr-179, in the second extracellular loop (ECL2) and Trp-4007.35 in transmembrane domain (TM) 7. Collectively, this study highlights how the properties of affinity and cooperativity can be differentially modified on a common structural scaffold and identifies molecular features that can be exploited to tailor the development of M1 mAChR-targeting PAMs. 相似文献
12.
《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
13.
A novel series of N-benzylpyridinium moiety linked to arylisoxazole ring were designed, synthesized, and evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Synthesized compounds were classified into two series of 5a-i and 5j-q considering the position of positively charged nitrogen of pyridinium moiety (3- or 4- position, respectively) connected to isoxazole carboxamide group. Among the synthesized compounds, compound 5n from the second series of compounds possessing 2,4-dichloroaryl group connected to isoxazole ring was found to be the most potent AChE inhibitor (IC50 = 5.96 µM) and compound 5j also from the same series of compounds containing phenyl group connected to isoxazole ring demonstrated the most promising inhibitory activity against BChE (IC50 = 0.32 µM). Also, kinetic study demonstrated competitive inhibition mode for both AChE and BChE inhibitory activity. Docking study was also performed for those compounds and desired interactions with those active site amino acid residues were confirmed through hydrogen bonding as well as π-π and π-anion interactions. In addition, the most potent compounds were tested against BACE1 and their neuroprotectivity on Aβ-treated neurotoxicity in PC12 cells which depicted negligible activity. It should be noted that most of the synthesized compounds from both categories 5a-i and 5j-q showed a significant selectivity toward BChE. However, series 5j-q were more active toward AChE than series 5a-i. 相似文献
14.
Aaron M. Bender Rebecca L. Weiner Vincent B. Luscombe Hyekyung P. Cho Colleen M. Niswender Darren W. Engers Thomas M. Bridges P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(11):2479-2483
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 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 M4 (IC50s < 300 nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma Kp,uu = 0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp = 5.37 mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M1–5, 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. 相似文献
15.
Hao Zhang Jin Wang Hong-Yi Zhao Xue-Yan Yang Hao Lei Minhang Xin Yong-Xiao Cao San-Qi Zhang 《Bioorganic & medicinal chemistry》2018,26(12):3619-3633
In the present study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC50 values of 0.025?μM and 0.49?μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFRL858R (IC50?=?1.7?nM) and EGFRL858R/T790M (IC50?=?23.3?nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50?mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents. 相似文献
16.
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
17.
《Bioorganic & medicinal chemistry letters》2019,29(14):1825-1830
In the present study, a series of newer benzothiazole derivatives containing thiazolidin-4-one (5a-g) and azetidin-2-one (6a-g), were synthesized by the cyclization of benzothiazolyl arylidene hydrazine carboxamide derivatives with thioglycolic acid and chloroacetyl chloride, respectively. Results of in vivo anticonvulsant screening revealed that compounds having 2,4-dicholoro (5c and 6c) and 4-nitro substituent (5g) at the phenyl ring have promising anticonvulsant activities without any neurotoxicity. Selected compounds were also evaluated for their in vitro GABA AT inhibition. The results indicated that compound 5c (IC50 15.26 μM) exhibited excellent activity as compared to the standard drug vigabatrin (IC50 39.72 μM) suggesting the potential of these benzothiazole analogues as new anticonvulsant agents. 相似文献
18.
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
19.
《Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis》1978,517(2):517-526
Using a combination of ultraviolet-visible absorption, 1H NMR and ESR techniques we have established that N(1) of the imidazole and N(1) of the pyrimidine residues of bleomycin A2 bind to Cu(II) and Zn(II). These observations coupled with the earlier results that the α-amino group of the α-amino carboxamide function and the carbamoyl moiety are also Cu(II)-ligating groups makes it possible to reconstruct the detailed geometry and stereochemistry of the metal binding site of bleomycin A2. 相似文献
20.
Bruce J. Melancon Michael S. Poslusney Patrick R. Gentry James C. Tarr Douglas J. Sheffler Margrith E. Mattmann Thomas M. Bridges Thomas J. Utley J. Scott Daniels Colleen M. Niswender P. Jeffrey Conn Craig W. Lindsley Michael R. Wood 《Bioorganic & medicinal chemistry letters》2013,23(2):412-416
This Letter describes the continued optimization of an MLPCN probe molecule (ML137) with a focused effort on the replacement/modification of the isatin moiety present in this highly selective M1 PAM. A diverse range of structures were validated as viable replacements for the isatin, many of which engendered sizeable improvements in their ability to enhance the potency and efficacy of acetylcholine when compared to ML137. Muscarinic receptor subtype selectivity for the M1 receptor was also maintained. 相似文献