Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2025 Jun 17;16(7):1231–1238. doi: 10.1021/acsmedchemlett.5c00271

Discovery of a Novel sp3‑Rich M1 Positive Allosteric Modulators (PAMs) Chemotype via Scaffold Hopping

Joseph D Bungard †,‡, Paul Spearing †,‡, Yu Nishio †,‡, Upendra Rathnayake †,‡, Chris C Presley †,‡, Sichen Chang †,‡, Haley E Kling †,‡, Analisa D Thompson †,‡, Hyekyung P Cho †,‡, Li Peng †,‡, Alice L Rodriguez †,‡, Colleen M Niswender †,‡,§,∥, Olivier Boutaud †,‡, Valerie Kramlinger †,‡, Carrie K Jones †,‡, P Jeffrey Conn †,‡,§, Julie L Engers †,‡, Darren W Engers †,‡,*, Craig W Lindsley †,‡,∥,⊥,*, Changho Han †,‡,*
PMCID: PMC12257413  PMID: 40666451

Abstract

The M1 receptor has long been investigated as a promising CNS drug target, yet further research is essential to fully elucidate compound’s Pharmacodynamic (PD) as well as Toxicokinetic (TK) effects. In this context, the development of structurally diverse and high-profile M1 PAM tool compounds remains highly valuable, as existing advanced tools exhibit notable structural similarity. One approach that can be considered during scaffold hopping exercise and can improve drug-like properties is to introduce additional sp3 carbon atoms and increase Fsp3 values; the fraction of sp3 hybridized carbons. Determining the correct location to incorporate sp3 carbon atoms can be challenging, but once the right position is identified, it often leads to novel optimization opportunities. Reported herein is the discovery of a novel sp3-rich M1 positive allosteric modulator series utilizing a N-cyclopentyl pyrazole core. Also, an iterative library synthesis approach provided an enhanced understanding of the minimum pharmacophore. Several compounds within the series showed favorable on-target potencies and DMPK properties. In conclusion, the reported sp3-rich N-cyclopentyl pyrazole-based M1 PAM scaffold offers a promising structure–activity relationship starting point to discover structurally distinct M1 PAM chemotypes.

Keywords: GPCR, positive allosteric modulator, M1 PAM, pyrazole, Fsp3

graphic file with name ml5c00271_0011.jpg

graphic file with name ml5c00271_0010.jpg

Alzheimer’s disease (AD) is a neurodegenerative disease that affects millions of individuals worldwide and accounts for roughly 60–80% of dementia cases. As Alzheimer’s disease progresses, various pathological changes provide logical evidence for cognitive decline and memory loss. These events include aggregation of amyloid β (Aβ), production of neurofibrillary tangles (NFT) from phosphorylation of tau, and reduction in the synthesis of acetylcholine (ACh). − The cholinergic system has long been considered a target for the treatment of AD and other neurological disorders due to the ubiquitous nature of ACh within the central nervous system (CNS), and its role in pathways related to memory and cognition. Cholinergic signal transduction is mediated by muscarinic and nicotinic ACh receptors, and muscarinic ACh receptors (mAChRs) are considered important drug targets.

There are five different subtypes of G protein-coupled mAChRs. Of the five mAChR subtypes M1–M5, M1 is most abundantly expressed in the brain, particularly in the hippocampus and prefrontal cortex, locations associated with memory and cognition. , Additionally, selective activation of M1 enhances α-secretase activity which promotes the development of sAPPα, a protein that prevents the formation of Aβ plaques and makes M1 an attractive target for neurodegenerative diseases, such as AD.

Since Xanomeline, an M1/M4 preferring agonist, was first discovered in the early 1990s, much effort has been made to discover highly selective M1 activators and potentiators. As a result, various subtype-selective M1 positive allosteric modulators (PAMs) have been reported (Figure ). − These chemotypes can be classified into three different categories: 1) chemotypes that utilize an intramolecular hydrogen bond to orient the amide carbonyl moiety, a key pharmacophore, in a bioactive conformation; 2) chemotypes that cyclize the amide to form a formalized ring; 3) structurally distinct chemotypes. However, selective M1 PAM compounds without undesired adverse events remain elusive.

1.

1

Open in a new tab

Selected M1 PAMs that have been reported in the public domain and their Fsp3 values; 1 11, 2 12, 3 13, 4 14, 5 15, 6 16, 7 17, 8 18, 9 19, 10 20, 11 21, and 12 22.

As shown in Figure , the majority of reported M1 PAM chemotypes share structural similarities except for a few such as 9–12, and most of these chemotypes share low Fsp3, a recently highlighted drug-likeness parameter that describes the fraction of sp3 hybridized carbons in a drug molecule. , Although a higher Fsp3 value by itself cannot serve as a predictor of overall drug-likeness and in vivo efficacy, over 80% of marketed drugs exhibit Fsp3 ≥ 0.42, indicating the potential importance of Fsp3 as a parameter to consider during the lead optimization stage. Thus far, only a small number of M1 PAMs have Fsp3 ≥ 0.42. Moreover, many advanced M1 PAM tool compounds are structurally related, sharing only a narrow chemical space. Given the complex nature of M1 pharmacology and M1-mediated adverse events, a better understanding of M1 biology through potent, selective, yet structurally diverse M1 PAM tools is essential for successful clinical trials.

To date, numerous scaffold-hopping efforts have been made in M1 PAM discovery to identify novel chemotypes. However, introducing an sp3-rich moiety into the molecule has proven quite difficult, as the M1 PAM binding site predominantly accommodates chemotypes with sp2-hybridized structures. Despite these challenges, our efforts to find a new starting point continued, as a fundamentally different scaffold containing a unique sp3-rich core could provide us with unique opportunities and ADMET profiles.

Recently, scientists at Monash Institute for Pharmaceutical Sciences (MIPS) reported an interesting 6-phenylpyrimidin-4­(3H)-one-based scaffold, as featured in 5 (Figure ), which evolved from 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA). As shown in Figure , we hypothesized that a novel chemotype with a potential new SAR point could be generated from a scaffold hopping exercise (or hybridization exercise) between 3 and 5. During the rationalized design process, we suspected that the core size might require reduction as a rather large phenyl ring had been introduced. Therefore, the pyrazole ring was designed instead of the pyridine ring. In general, pyrazoles are metabolically stable and interact with biological targets through hydrogen bonding, making them versatile structures in the realm of medicinal chemistry. We envisioned that this new chemotype could not only provide unique SAR opportunities but also provide a desirable steric repulsion against the benzylic tail. Additionally, the nitrogen atom from the pyrazole ring would allow intramolecular hydrogen bond formation with the amide N–H that stabilizes the bioactive conformer.

2.

2

Open in a new tab

Rationalized design of the novel M1 mAChR PAM scaffold contains a potential new SAR opportunity.

The synthesis of the designed novel core was straightforward (Scheme ). The synthesis commenced through the treatment of diketoester 13 with various alkyl hydrazines in EtOH at 80 °C to provide the corresponding alkylated pyrazole subunits in 14 in good yield (64–84%). The resulting olefins were then oxidatively cleaved with OsO4 and NMO and subsequently treated with NaIO4 to provide the corresponding aldehyde intermediates. Reduction of the aldehydes with NaBH4 in MeOH at 0 °C furnished the resulting pyrazole alcohols 15 in good yields. Conversion of the alcohols to the bromide derivative with PBr3 at 0 °C, followed by a Suzuki-Miyaura coupling with the appropriate boronic ester and Pd­(dppf)­Cl2·DCM at 80 °C provided analogs 16. Hydrolysis of the ethyl ester and HATU-mediated amide coupling reactions afforded the M1 PAM analogs 17 in yields of 11–61% over the course of two steps.

1. Synthesis of Pyrazole Analogs 17 .

1

Open in a new tab

a Reagents and conditions: (a) R1NHNH2·HCl, EtOH, 80 °C, 2 h, 64-84%; (b) OsO4, NMO, THF/H2O, 0 °C–RT overnight, then NaIO4; (c) NaBH4, MeOH, 0 °C, 2 h, 80-88% over 2 steps; (d) PBr3, DCM, 0 °C, 1 h; (e) Aryl boronic ester, Pd­(dppf)­Cl2·DCM, Cs2CO3, 1,4-Dioxane/H2O, 80 °C, 13–28% over 2 steps; (f) LiOH, THF, RT overnight, quantitative; (g) R3NH2, HATU, DIPEA, DMF, RT, 11–61% over 2 steps.

Because of the size of the phenyl ring, we suspected the binding pose could be frame-shifted to the right (Figure ). In this case, the historically preferred cyclohexanol and tetrahydro-2H-pyran-3-ol next to the amide linkage may not be the optimal substituent, and a smaller ring might be more desirable. Therefore, we synthesized a set of compounds with a variety of ring sizes (Table ). Because rats are used in our preclinical pharmacodynamic models, the ideal chemotype should not have a huge species disconnect. Therefore, newly synthesized compounds were then tested against both human and rat M1 mAChrs in parallel.

1. Initial Compound Library and SAR Evaluation of N-Phenyl Pyrazoles.

graphic file with name ml5c00271_0007.jpg

Open in a new tab
a

Calcium mobilization assays in rM1 and hM1-CHO cells were performed in the presence of an EC20 fixed concentration of acetylcholine for PAM activity.

b

Each independent experiment was performed in duplicate or triplicate.

Despite the sensitive SAR nature of the PAM binding site, 17a and 17b retained modest potencies in the low micromolar range (hM1 pEC50 = 5.52 ± 0.12 and 5.70 ± 0.07, respectively). In contrast to our hypothesis, smaller rings containing analogs 17c and 17d displayed a slight loss of potency (hM1 pEC50 < 5). This potentially indicates that the binding pose of analogs containing an N-phenyl pyrazole core may still be similar to those of the historical compounds or may be unexpectedly shifted to the left. To confirm our hypothesis, we synthesized a larger ring containing analog 17e. It was slightly less potent compared to 17a and 17b, indicating that the binding pose might remain very similar to the previously reported series (17e, hM1 pEC50 = 5.34 ± 0.18). From these results, we maintained­(3R,4S)-4-aminotetrahydro-2H-pyran-3-ol as an optimal substituent and shifted attention to surveying additional substituents from the pyrazole core.

Since π–π interactions have been revealed as major driving forces between GPCR allosteric sites and PAM ligands (Figure ), only flat and aromatic motifs tend to be considered as alternative cores, assuming M1 PAMs may have similar binding poses compared to LY2119620. Indeed, subsequent structure–activity relationship studies as well as docking studies in the allosteric site of the M1 homology model suggested M1 PAMs may have similar binding poses compared to LY2119620. Therefore, we initially speculated that the N-phenyl pyrazole moiety was essential for activity because it is also flat and aromatic. In addition, only small aromatic heterocycles that have minimal effect on the π–π interaction between the core and tryptophan residue may be tolerated as N-pyrazole substituents. However, as shown in Table , Fsp3 values of N-phenyl pyrazole analogs were already much lower than 0.42 in general (0.24–0.32). Therefore, to improve pharmaceutical properties by enhancing the sp3 character, we decided to challenge the aforementioned dogma and introduce the sp3 character off of the pyrazole core. Besides, there is always a possibility that different M1 PAM chemotypes could have slightly different binding poses and interact with different residues.

3.

3

Open in a new tab

Binding site illustration of LY2119620 (an M2/M4 PAM). (A) The binding mode of LY2119620 in M2 receptor (PDB: 4MQT). LY2119620 was crystallized in complex with M2 receptor along with the orthosteric agonist, iperoxo, for the first time. (B) 2D interaction diagram of LY2116920. The π–π interaction has been considered an important driving force for compound binding at the GPCR PAM binding site based on the π–π interaction between Trp422 and 7-aza-benzothiophene motif of LY2119620.

While homologation by one carbon with a methylene linker was not tolerated (17f, hM1 pEC50 < 5), 17g with an sp3-rich cyclopentyl ring afforded enhanced activity (rM1 pEC50 = 6.46 ± 0.03, hM1 pEC50 = 6.37 ± 0.08) compared to the respective N-benzyl and N-phenyl counterparts (Table , 17f–17j). We were encouraged by this surprising result and overlaid 17g with 5 and 7 (Figure ). From the overlay shown in Figure , we suspected that the slightly larger cyclohexyl ring might be suboptimal compared to the cyclopentyl ring because the cyclopentyl ring was already slightly larger than the phenyl ring of 17b. Not surprisingly, 17h with a cyclohexyl ring was notably weaker compared to 17g (17h, rM1 pEC50 = 5.83 ± 0.09, hM1 pEC50 = 5.31 ± 0.12).

2. SAR Evaluation of N-Substitution of a Pyrazole Core.

graphic file with name ml5c00271_0008.jpg

Open in a new tab
a

Calcium mobilization assays with rM1 and hM1-CHO cells performed in the presence of an EC20 fixed concentration of acetylcholine for PAM activity.

b

Each independent experiment was performed in duplicate or triplicate.

4.

4

Open in a new tab

Structural overlay between 5, 7, and 17g. Structures were overlaid via the flexible alignment function using Molecular Operating Environment (MOE).

Based on this SAR trend, we hypothesized that a truncation of the cyclopentyl ring to isopropyl moiety may also be tolerated because the size of the isopropyl moiety may lie between the sizes of phenyl and methyl substituents. However, 17i with the isopropyl substituent was inactive. Interestingly, our attempt to replace the cyclopentyl ring with a five-membered heterocycle, tetrahydrofuran, was well tolerated (17j, rM1 pEC50 = 6.25 ± 0.08, hM1 pEC50 = 5.92 ± 0.01), and subsequent efforts such as a chiral resolution were warranted. Additional SAR information will be reported in due course.

Because the binding pose might be changed with a sp3-rich substituent, we reinvestigated the amide substitution before shifting our attention to the tail. For second-generation amide libraries with an N-cyclopentyl pyrazole core, the amines tolerated in the previous amide scanning exercise (Table ) were initially focused on (Table , 17k–17m). While N-cyclopentyl pyrazole analogs consistently showed improved potencies compared to those of N-phenyl pyrazole analogs, potency trends were the same ((3R,4S)-4-aminotetrahydro-2H-pyran-3-ol (17g) > (1S,2S)-2-aminocyclohexan-1-ol (17k) > (1S,2S)-2-aminocycloheptan-1-ol (17l) > (1S,2S)-2-aminocyclopentan-1-ol) (17m). While there is still room for improvement, 17g and 17k showed the best potential with enhanced Fsp3 values (hM1 pEC50 = 6.37 ± 0.08 and 6.23 ± 0.01; Fsp3 = 0.48 and 0.50, respectively). In addition, historically less favored amides were also tested to reconfirm the SAR trends (17n–17p). As expected, 17n–17p showed much weaker potencies compared to the aforementioned preferred amines. Due to the sp3-rich character of a cyclopentyl moiety, synthesized analogs tended to have higher Fsp3 values (Fsp3 = 0.46–0.52) compared to previously reported M1 PAMs (Figure ).

3. Amide Library Reinvestigation with sp3-Rich N-Cyclopentyl Pyrazole Core.

graphic file with name ml5c00271_0009.jpg

Open in a new tab
a

Calcium mobilization assays with rM1 and hM1-CHO cells performed in the presence of an EC20 fixed concentration of acetylcholine for PAM activity.

b

Each independent experiment was performed in duplicate or triplicate.

Lastly, our SAR interest shifted to the investigation of heterobiaryl tails. As shown in Figure , most of the previously highlighted M1 PAMs contain heterobiaryl tails. While heterobiaryl moieties are easy to synthesize via Suzuki-Miyaura coupling, the sp2-rich character of heterobiaryl moieties is often detrimental to pharmaceutical properties. Therefore, we replaced sp2-rich heterobiaryl tails with those containing fewer sp2 carbons. Based on the literature review and our SAR knowledge, substituted benzamides were selected as a heterobiaryl replacement. While simple benzamides contain fewer sp2 carbons, they are well tolerated in other series (Figure A). Additionally, our previous amide libraries indicate no notable shift in the binding pose. Therefore, we anticipated simple benzamides would be tolerated in our novel chemotype as well (Figure B). Although detailed SAR discussion is beyond the scope of the current report and will be reported in due course, 21 from the initial library showed encouraging potency (21, rM1 pEC50 = 6.10 ± 0.04, hM1 pEC50 = 5.90 ± 0.13). In particular, Fsp3 values of N-cyclopentyl pyrazole analogs were much higher than 0.42 (21, Fsp3 = 0.52), suggesting the possibility of improved overall pharmaceutical properties.

5.

5

Open in a new tab

Heterobiaryl tail replacement with substituted benzamides (A) Exemplary compound with benzamide tails 18, 19, and 20. (B) Novel sp3-rich M1 PAM.

With novel, sp3-rich M1 PAMs in hand, several compounds were selected for Tier 1 DMPK profiling (Table ). Selected M1 PAMs displayed promising physiochemical properties: MW < 500, TPSA < 100, and cLogP < 5. Notably, aqueous solubilities were improved with higher Fsp.3 Rat in vivo Tier 1 DMPK profiles from PK/PBL cassette studies also suggested that this chemotype was promising as a new starting point. While 17k was significantly more CNS penetrant (17k, Kp = 0.63; 17g, Kp = 0.12), 17g showed promising aqueous solubilities in both pHs (17g, 84.6 μM at pH 2.2, 80.7 μM at pH 6.8).

4. Detailed In Vitro and In Vivo Profiles for Selected M1 PAMs .

Property 17k 17g
MW 447 449
cLogP 4.61 3.15
TPSA 85 94.2
Fsp3 0.50 0.48
Solubility
pH = 2.2 10.8 μM 84.6 μM
pH = 6.8 <1.12 μM 80.7 μM
ElogD 7.4 4.15 3.05
In Vitro PK
Rat CLHEP (mL/min/kg) 49.5 32.8
Human CLHEP (mL/min/kg) 14.3 6.7
Human fuplasma 0.01 0.08
Rat fuplasma 0.03 0.08
Rat fubrain 0.01 0.08
In Vivo PK (PK/PBL cassette)
t 1/2 (h) 0.63 1.21
MRT (h) 0.65 1.28
CLp (mL/min/kg) 56 20.8
Vss (L/kg) 2.2 1.59
AUC (h*ng/mL) 74.4 160
Kp 0.63 0.12
Open in a new tab
a

In the case of 17k, t 1/2 was 0.63 h with MRT of 0.65 h. CLp was 56 mL/min/kg, Vss was 2.2 L/kg, and AUC was 74.4 h*ng/mL. Interestingly, slightly more polar 17g showed lower clearance profiles compared to 17k. t 1/2 was 1.21 h with MRT of 1.28 h. CLp was 20.8 mL/min/kg, Vss was 1.59 L/kg, and AUC was 160 h*ng/mL.

In conclusion, a series of novel pyrazole-based M1 PAMs was discovered from a rationalized scaffold-hopping approach. Pyrazole structures offered unprecedented SAR opportunities and led to the discovery of N-cyclopentyl pyrazole as a novel minimum pharmacophore. Sp3-rich character positively influenced pharmaceutical properties and offered a promising compound for further optimization. Detailed SAR discussion, along with DMPK profiles within the series, will be reported in a timely manner.

Supplementary Material

ml5c00271_si_001.pdf (2.4MB, pdf)

Acknowledgments

The authors thank William K. Warren, Jr. who funded the William K. Warren, Jr. Chair in Medicine (C.W.L.) and the William K. Warren Foundation for endowing the Warren Center for Neuroscience Drug Discovery.

Glossary

Abbreviations

ADMET

absorption, distribution, metabolism, excretion, and toxicity

AUC

area under the curve

CHO

Chinese hamster ovary

CLp

plasma clearance

CLHEP

hepatic clearance

DMPK

drug metabolism pharmacokinetics

fuplasma

fraction unbound in plasma

fubrain

fraction unbound in brain

GPCR

G-protein-coupled receptor

HATU

hexafluorophosphate azabenzotriazole tetramethyl uronium

Kp

brain/plasma ratio

MW

molecular weight

MRT

mean residence time

NMO

4-methylmorpholine N-oxide

PBL

plasma:brain level

PAM

positive allosteric modulator

SAR

structure activity relationship

TPAS

topological polar surface area

Vss

volume of distribution at steady state

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00271.

  • General chemistry, experimental information, and syntheses of all other compounds; in vitro and in vivo pharmacology and DMPK methods; supplementary figures and table (PDF)

J.D.B., P.S., Y.N., U.R., and C.C.P. performed synthetic chemistry and compound characterization. H.E.K., L.P., A.L.R., H.P.C., and C.M.N. performed and analyzed molecular pharmacology experiments. S.C., O.B., V.K., A.D.T., and C.K.J. performed and analyzed PK experiments. C.W.L., D.W.E., J.L.E., C.H., H.P.C., O.B., V.K., and P.J.C. oversaw experimental design. C.H. wrote the manuscript with input from all authors.

Acadia Pharmaceuticals.

The authors declare the following competing financial interest(s): Some authors are inventors in the application for the composition of matter patents that protect several series of M1 PAMs. Some authors have received royalties from Acadia Pharmaceuticals.

References

  1. DeTure M. A., Dickson D. W.. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 2019;14(1):32. doi: 10.1186/s13024-019-0333-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Singh S. K., Srivastav S., Yadav A. K., Srikrishna S., Perry G.. Overview of Alzheimer’s disease and some therapeutic approaches targeting Aβ by using several synthetic and herbal compounds. Oxid Med. Cell Longev. 2016;2016:7361613. doi: 10.1155/2016/7361613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Nie Q., Du X.-G., Geng M.-Y.. Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer’s disease. Acta Pharmacol Sin. 2011;32(5):545–551. doi: 10.1038/aps.2011.14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Jiang S., Li Y., Zhang C., Zhao Y., Bu G., Xu H., Zhang Y. W.. M1 muscarinic acetylcholine receptor in Alzheimer’s disease. Neurosci Bull. 2014;30(2):295–307. doi: 10.1007/s12264-013-1406-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Haam J., Yakel J. L.. Cholinergic modulation of the hippocampal region and memory function. J. Neurochem. 2017;142(Suppl 2):111–121. doi: 10.1111/jnc.14052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Langmead C. J., Watson J., Reavill C.. Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther. 2008;117(2):232–243. doi: 10.1016/j.pharmthera.2007.09.009. [DOI] [PubMed] [Google Scholar]
  7. Thompson R. F., Kim J. J.. Memory systems in the brain and localization of a memory. Proc. Natl. Acad. Sci. U. S. A. 1996;93(24):13438–13444. doi: 10.1073/pnas.93.24.13438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Shiozaki K., Iseki E., Hino H., Kosaka K.. Distribution of M1 muscarinic acetylcholine receptors in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies-an immunohistochemical study. J. Neurol Sci. 2001;193(1):23–28. doi: 10.1016/S0022-510X(01)00638-4. [DOI] [PubMed] [Google Scholar]
  9. Huang M., Suk D.-H., Cho N.-C., Bhattarai D., Kang S. B., Kim Y., Pae A. N., Rhim H., Keum G.. Synthesis and biological evaluation of isoxazoline derivatives as potent M1 muscarinic acetylcholine receptor agonists. Bioorg. Med. Chem. Lett. 2015;25(7):1546–1551. doi: 10.1016/j.bmcl.2015.02.012. [DOI] [PubMed] [Google Scholar]
  10. Sauerberg P., Olesen P. H., Nielsen S., Treppendahl S., Sheardown M. J., Honoré T., Mitch C. H., Ward J. S., Pike A. J., Bymaster F. P.. et al. Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines. J. Med. Chem. 1992;35(12):2274–2283. doi: 10.1021/jm00090a019. [DOI] [PubMed] [Google Scholar]
  11. Davoren J. E., O’Neil S. V., Anderson D. P., Brodney M. A., Chenard L., Dlugolenski K., Edgerton J. R., Green M., Garnsey M., Grimwood S.. et al. Design and optimization of selective azaindole amide M1 positive allosteric modulators. Bioorg. Med. Chem. Lett. 2016;26(2):650–655. doi: 10.1016/j.bmcl.2015.11.053. [DOI] [PubMed] [Google Scholar]
  12. Nirogi, R. ; Mohammed, A. R. ; Shinde, A. K. ; Ravella, S. R. ; Subramanian, R. ; Jasti, V. . Pyrrolo-pyridazine derivatives as muscarinic M1 receptor positive allosteric modulators. 2021. WO2020079606A9.
  13. Davoren J. E., Lee C. W., Garnsey M., Brodney M. A., Cordes J., Dlugolenski K., Edgerton J. R., Harris A. R., Helal C. J., Jenkinson S.. et al. Discovery of the potent and selective M1 PAM-agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)­benzyl]­pyridine-2-carboxamide (PF-06767832): evaluation of efficacy and cholinergic side effects. J. Med. Chem. 2016;59(13):6313–6328. doi: 10.1021/acs.jmedchem.6b00544. [DOI] [PubMed] [Google Scholar]
  14. Rook J. M., Bertron J. L., Cho H. P., Garcia-Barrantes P. M., Moran S. P., Maksymetz J. T., Nance K. D., Dickerson J. W., Remke D. H., Chang S.. et al. A novel M1 PAM VU0486846 exerts efficacy in cognition models without displaying agonist activity or cholinergic toxicity. ACS Chem. Neurosci. 2018;9(9):2274–2285. doi: 10.1021/acschemneuro.8b00131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mistry S. N., Jörg M., Lim H., Vinh N. B., Sexton P. M., Capuano B., Christopoulos A., Lane J. R., Scammells P. J.. 4-Phenylpyridin-2-one derivatives: a novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor. J. Med. Chem. 2016;59(1):388–409. doi: 10.1021/acs.jmedchem.5b01562. [DOI] [PubMed] [Google Scholar]
  16. Beshore D. C., N Di Marco C., Chang R. K., Greshock T. J., Ma L., Wittmann M., Seager M. A., Koeplinger K. A., Thompson C. D., Fuerst J.. et al. MK-7622: A first-in-class M1 positive allosteric modulator development candidate. ACS Med. Chem. Lett. 2018;9(7):652–656. doi: 10.1021/acsmedchemlett.8b00095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Davoren J. E., Garnsey M., Pettersen B., Brodney M. A., Edgerton J. R., Fortin J. P., Grimwood S., Harris A. R., Jenkinson S., Kenakin T.. et al. Design and synthesis of γ- and δ-lactam M1 positive allosteric modulators (PAMs): convulsion and cholinergic toxicity of an M1-selective PAM with weak agonist activity. J. Med. Chem. 2017;60(15):6649–6663. doi: 10.1021/acs.jmedchem.7b00597. [DOI] [PubMed] [Google Scholar]
  18. Yang Z. Q., Shu Y., Ma L., Wittmann M., Ray W. J., Seager M. A., Koeplinger K. A., Thompson C. D., Hartman G. D., Bilodeau M. T.. et al. Discovery of naphthyl-fused 5-membered lactams as a new class of M1 positive allosteric modulators. ACS Med. Chem. Lett. 2014;5(5):604–608. doi: 10.1021/ml500055h. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moran S. P., Dickerson J. W., Cho H. P., Xiang Z., Maksymetz J., Remke D. H., Lv X., Doyle C. A., Rajan D. H., Niswender C. M.. et al. M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition. Neuropsychopharmacology. 2018;43(8):1763–1771. doi: 10.1038/s41386-018-0033-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Tarr J. C., Turlington M. L., Reid P. R., Utley T. J., Sheffler D. J., Cho H. P., Klar R., Pancani T., Klein M. T., Bridges T. M.. et al. Targeting selective activation of M(1) for the treatment of Alzheimer’s disease: further chemical optimization and pharmacological characterization of the M(1) positive allosteric modulator ML169. ACS Chem. Neurosci. 2012;3(11):884–895. doi: 10.1021/cn300068s. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Swinnen, D. ; Montagne, C. ; Pomel, V. ; Quattropani, A. ; Molette, J. ; Gerber, P. . Tetraaza-cyclopenta­[a]­indenyl derivatives as M1 receptor positive allosteric modulators useful in the treatment of diseases mediated by the muscarinic M1 mediator and their preparation. 2013.
  22. Sugimoto, T. ; Shimokawa, K. ; Kojima, T. ; Sakamoto, H. ; Fujimori, I. ; Nakamura, M. ; Yamada, M. ; Murakami, M. ; Kamata, M. ; Suzuki, S. . Nitrogen-containing heterocyclic compounds and their use for pharmaceuticals and cholinergic muscarinic M1 receptor positive allosteric modulation. 2015. WO2014077401A1.
  23. Wei W., Cherukupalli S., Jing L., Liu X., Zhan P.. Fsp3: A new parameter for drug-likeness. Drug Discov Today. 2020;25(10):1839–1845. doi: 10.1016/j.drudis.2020.07.017. [DOI] [PubMed] [Google Scholar]
  24. Kombo D. C., Tallapragada K., Jain R., Chewning J., Mazurov A. A., Speake J. D., Hauser T. A., Toler S.. 3D molecular descriptors important for clinical success. J. Chem. Inf Model. 2013;53(2):327–342. doi: 10.1021/ci300445e. [DOI] [PubMed] [Google Scholar]
  25. Naim M. J., Alam O., Nawaz F., Alam M. J., Alam P.. Current status of pyrazole and its biological activities. J. Pharm. Bioallied Sci. 2016;8(1):2–17. doi: 10.4103/0975-7406.171694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kruse A. C., Ring A. M., Manglik A., Hu J., Hu K., Eitel K., Hubner H., Pardon E., Valant C., Sexton P. M.. et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature. 2013;504(7478):101–106. doi: 10.1038/nature12735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sakai, S. ; Seto, M. ; Takami, K. ; Ando, H. . Preparation of heterocyclic threo-pentitol compounds useful as modulators of acetylcholine receptors. 2018. WO2018194181A1.
  28. Sasaki, S. ; Asano, Y. ; Takami, K. ; Seto, M. ; Ando, H. . Preparation of N-(3-hydroxytetrahydro-2H-pyran-4-yl)-4-methyl-2,3-dihydrobenzofuran-7-carboxamide derivatives as positive allosteric modulators of muscarinic acetylcholine receptor M1 . 2020. WO2020067456A1.
  29. Takami, K. ; Seto, M. ; Sasaki, S. ; Ando, H. ; Ogino, M. ; Ohashi, T. ; Imaeda, T. ; Fujimori, I. ; Tsukimi, Y. ; Yamada, M. ; et al. Preparation of 2,3-dihydrofuro­[3,2-b]­pyridine-5-carboxamide as cholinergic muscarinic M1 receptor positive allosteric modulators. 2018.WO2018235838A1.
  30. Lovering F., Bikker J., Humblet C.. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009;52(21):6752–6756. doi: 10.1021/jm901241e. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml5c00271_si_001.pdf (2.4MB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES