From Wikipedia, the free encyclopedia
Chemical compound
Mevidalen
Other names LY-3154207; LY3154207
2-(2,6-dichlorophenyl)-1-[(1S ,3R )-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydro-1H -isoquinolin-2-yl]ethanone
CAS Number
PubChem
CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
Formula C 24 H 29 Cl 2 N O 3
Molar mass 450.40 g·mol−1 3D model (
JSmol )
C[C@H]1C2=CC=CC(=C2C[C@@H](N1C(=O)CC3=C(C=CC=C3Cl)Cl)CO)CCC(C)(C)O
InChI=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
Key: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]
[5] It acts as a
selective
positive allosteric modulator (PAM) of the
dopamine
D1 receptor .
[1]
[6] The drug is
orally active and crosses the
blood–brain barrier .
[6] It is a
tetrahydroisoquinoline and is a close
analogue of DETQ, another D1 receptor PAM.
[2]
[3]
[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.
[6]
[5]
[8] As of March 2022, mevidalen is in
phase 2
clinical trials for the treatment of Lewy body disease.
[1] 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 .
[2]
References
^
a
b
c
"Mevidalen - Eli Lilly and Company" . AdisInsight . Springer Nature Switzerland AG.
^
a
b
c Svensson KA, Hao J, Bruns RF (2019). "Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders". Advances in Pharmacology . Advances in Pharmacology. Vol. 86. San Diego, Calif.: Elsevier. pp. 273–305.
doi :
10.1016/bs.apha.2019.06.001 .
ISBN
9780128166680 .
ISSN
1054-3589 .
PMID
31378255 .
S2CID
199071223 .
^
a
b Hao J, Beck J, Zhou X, Lackner GL, Johnston R, Reinhard M, et al. (March 2022). "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.
doi :
10.1021/acs.jmedchem.1c01887 .
PMID
35175768 .
S2CID
246942987 .
^ Biglan K, Munsie L, Svensson KA, Ardayfio P, Pugh M, Sims J, Brys M (March 2022).
"Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial" . Movement Disorders . 37 (3): 513–524.
doi :
10.1002/mds.28879 .
PMC
9300146 .
PMID
34859493 .
S2CID
244887088 .
^
a
b Wilbraham D, Biglan KM, Svensson KA, Tsai M, Pugh M, Ardayfio P, Kielbasa W (March 2022).
"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.
doi :
10.1002/cpdd.1039 .
PMC
9298003 .
PMID
34664427 .
S2CID
239028000 .
^
a
b
c
d Wilbraham D, Biglan KM, Svensson KA, Tsai M, Kielbasa W (April 2021).
"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.
doi :
10.1002/cpdd.874 .
PMC
8048550 .
PMID
33029934 .
^ Jones-Tabah J, Mohammad H, Paulus EG, Clarke PB, Hébert TE (2021).
"The Signaling and Pharmacology of the Dopamine D1 Receptor" . Frontiers in Cellular Neuroscience . 15 : 806618.
doi :
10.3389/fncel.2021.806618 .
PMC
8801442 .
PMID
35110997 .
^
a
b McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, et al. (March 2022).
"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.
doi :
10.1124/jpet.121.000719 .
PMID
34893551 .
S2CID
247363215 .