MK-7622

MK-7622
Clinical data
Drug classpositive allosteric modulator of M1 muscarinic receptor
Identifiers
  • 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methyl-3-pyridinyl)methyl]benzo[h]quinazolin-4-one
CAS Number
PubChem CID
DrugBank
UNII
ChEMBL
ECHA InfoCard100.209.716 Edit this at Wikidata
Chemical and physical data
FormulaC25H25N3O2
Molar mass399.494 g·mol−1
3D model (JSmol)
  • CC1=NC=C(C=C1)CC2=CC3=C(C4=CC=CC=C42)N=CN(C3=O)[C@H]5CCCC[C@@H]5O
  • InChI=1S/C25H25N3O2/c1-16-10-11-17(14-26-16)12-18-13-21-24(20-7-3-2-6-19(18)20)27-15-28(25(21)30)22-8-4-5-9-23(22)29/h2-3,6-7,10-11,13-15,22-23,29H,4-5,8-9,12H2,1H3/t22-,23-/m0/s1
  • Key:JUVQLZBJFOGEEO-GOTSBHOMSA-N

The MK-7622 is the first-of-its-kind oral positive allosteric modulator of M1 muscarinic receptors, developed by Merck for the treatment of Alzheimer’s disease, with a structure comprising a benzoquinazolinone bearing additional complex substituents at positions 3 and 6. MK-7622 failed to pass Phase II clinical trials for the treatment of Alzheimer's disease (as an adjunctive therapy) and has been withdrawn from production.

Pharmacology

Pharmacodynamics

MK-7622 acts as a highly selective positive allosteric modulator of the M1 muscarinic receptor; it exhibits the properties of an allosteric agonist and is characterised by a predominant enhancement of beta-arrestin-associated signalling rather than balanced modulation, which is the cause of some of its cholinergic side effects.

Side effects

Side effects included behavioural seizures and cognitive impairment.

References

  1. 1 2 Beshore DC, N Di Marco C, Chang RK, Greshock TJ, Ma L, Wittmann M, et al. (July 2018). "MK-7622: A First-in-Class M1 Positive Allosteric Modulator Development Candidate". ACS Medicinal Chemistry Letters. 9 (7): 652–656. doi:10.1021/acsmedchemlett.8b00095. PMC 6047034. PMID 30034595.
  2. 1 2 Uslaner JM, Kuduk SD, Wittmann M, Lange HS, Fox SV, Min C, et al. (June 2018). "Preclinical to Human Translational Pharmacology of the Novel M1 Positive Allosteric Modulator MK-7622". The Journal of Pharmacology and Experimental Therapeutics. 365 (3): 556–566. doi:10.1124/jpet.117.245894. PMID 29563325.
  3. 1 2 3 Nguyen HT, Khajehali E, Pham V, Scott JW, Dite TA, Dagley LF, et al. (July 2026). "Low Agonism and Balanced Pathway Modulation Distinguish an M1 Muscarinic Receptor Positive Allosteric Modulator Lacking Cholinergic Adverse Effects". ACS Chemical Neuroscience. 17 (14): 2641–2659. doi:10.1021/acschemneuro.6c00229. PMID 42376914.
  4. 1 2 3 Moran SP, Dickerson JW, Cho HP, Xiang Z, Maksymetz J, Remke DH, et al. (July 2018). "M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition". Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. 43 (8): 1763–1771. doi:10.1038/s41386-018-0033-9. PMC 6006294. PMID 29581537.
  5. 1 2 Rook JM, Bertron JL, Cho HP, Garcia-Barrantes PM, Moran SP, Maksymetz JT, et al. (September 2018). "A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity". ACS Chemical Neuroscience. 9 (9): 2274–2285. doi:10.1021/acschemneuro.8b00131. PMC 6146057. PMID 29701957.