Mevidalen Explained

Cas Number:1638667-79-4
Pubchem:86290953
Iuphar Ligand:10506
Chemspiderid:58985571
Unii:4A3702A96F
Kegg:D11826
Chembl:3421729
Synonyms:LY-3154207; LY3154207
Iupac Name:2-(2,6-dichlorophenyl)-1-[(1''S'',3''R'')-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydro-1''H''-isoquinolin-2-yl]ethanone
C:24
H:29
Cl:2
N:1
O:3
Smiles:C[C@H]1C2=CC=CC(=C2C[C@@H](N1C(=O)CC3=C(C=CC=C3Cl)Cl)CO)CCC(C)(C)O
Stdinchi:1S/C24H29Cl2NO3/c1-15-18-7-4-6-16(10-11-24(2,3)30)19(18)12-17(14-28)27(15)23(29)13-20-21(25)8-5-9-22(20)26/h4-9,15,17,28,30H,10-14H2,1-3H3/t15-,17+/m0/s1
Stdinchikey:XHCSBQBBGNQINS-DOTOQJQBSA-N

Mevidalen (developmental code name LY-3154207) is a dopaminergic drug which is under development for the treatment of Lewy body disease, including those with Parkinson's disease.[1] [2] [3] [4]

It acts as a selective positive allosteric modulator (PAM) of the dopamine D1 receptor. The drug is orally active and crosses the blood–brain barrier.[5] It is a tetrahydroisoquinoline and is a close analogue of DETQ, another D1 receptor PAM.[6]

Mevidalen has been found to have wakefulness-promoting effects in sleep-deprived humans.[7] [8] Side effects of mevidalen have been reported to include increased heart rate and blood pressure, insomnia, dizziness, nausea, vomiting, anxiety, nervousness, fatigue, headaches, palpitations, and contact dermatitis, as well as falls in those with dementia.

As of November 2023, mevidalen is in phase 2 clinical trials for the treatment of Lewy body disease. Besides for movement disorders and dementia, D1 receptor PAMs like mevidalen might have value in the treatment of certain neuropsychiatric disorders, such as depression, excessive somnolence, and attention deficit hyperactivity disorder (ADHD).

See also

Notes and References

  1. Web site: Mevidalen - Eli Lilly and Company . AdisInsight . Springer Nature Switzerland AG .
  2. Hao J, Beck J, Zhou X, Lackner GL, Johnston R, Reinhard M, Goldsmith P, Hollinshead S, Dehlinger V, Filla SA, Wang XS, Richardson J, Posada M, Mohutsky M, Schober D, Katner JS, Chen Q, Hu B, Remick DM, Coates DA, Mathes BM, Hawk MK, Svensson KA, Hembre E . 6 . Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug-Drug Interaction Risk Profile . Journal of Medicinal Chemistry . 65 . 5 . 3786–3797 . March 2022 . 35175768 . 10.1021/acs.jmedchem.1c01887 . 246942987 .
  3. Biglan K, Munsie L, Svensson KA, Ardayfio P, Pugh M, Sims J, Brys M . Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial . Movement Disorders . 37 . 3 . 513–524 . March 2022 . 34859493 . 9300146 . 10.1002/mds.28879 . 244887088 .
  4. Wilbraham D, Biglan KM, Svensson KA, Tsai M, Pugh M, Ardayfio P, Kielbasa W . Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator, in Patients With Parkinson Disease . Clinical Pharmacology in Drug Development . 11 . 3 . 324–332 . March 2022 . 34664427 . 9298003 . 10.1002/cpdd.1039 . 239028000 .
  5. Wilbraham D, Biglan KM, Svensson KA, Tsai M, Kielbasa W . Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects . Clinical Pharmacology in Drug Development . 10 . 4 . 393–403 . April 2021 . 33029934 . 8048550 . 10.1002/cpdd.874 .
  6. Book: Advances in Pharmacology . Svensson KA, Hao J, Bruns RF . Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders . Advances in Pharmacology . San Diego, Calif. . 2019 . 86 . 273–305 . Elsevier . 1054-3589 . 10.1016/bs.apha.2019.06.001 . 31378255 . 9780128166680 . 199071223 .
  7. Jones-Tabah J, Mohammad H, Paulus EG, Clarke PB, Hébert TE . The Signaling and Pharmacology of the Dopamine D1 Receptor . Frontiers in Cellular Neuroscience . 15 . 806618 . 2021 . 35110997 . 8801442 . 10.3389/fncel.2021.806618 . free .
  8. McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, Biglan KM, Wafford KA . 6 . The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers . The Journal of Pharmacology and Experimental Therapeutics . 380 . 3 . 143–152 . March 2022 . 34893551 . 10.1124/jpet.121.000719 . 247363215 . free .

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