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'''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]].<ref name="AdisInsight">https://adisinsight.springer.com/drugs/800042093</ref><ref name="SvenssonHaoBruns2019" /><ref name="pmid35175768">{{cite journal | vauthors = 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 | title = Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug-Drug Interaction Risk Profile | journal = J Med Chem | volume = 65 | issue = 5 | pages = 3786–3797 | date = March 2022 | pmid = 35175768 | doi = 10.1021/acs.jmedchem.1c01887 | url = }}</ref><ref name="pmid34859493">{{cite journal | vauthors = Biglan K, Munsie L, Svensson KA, Ardayfio P, Pugh M, Sims J, Brys M | title = Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial | journal = Mov Disord | volume = 37 | issue = 3 | pages = 513–524 | date = March 2022 | pmid = 34859493 | doi = 10.1002/mds.28879 | url = }}</ref><ref name="pmid34664427">{{cite journal | vauthors = Wilbraham D, Biglan KM, Svensson KA, Tsai M, Pugh M, Ardayfio P, Kielbasa W | title = Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator, in Patients With Parkinson Disease | journal = Clin Pharmacol Drug Dev | volume = 11 | issue = 3 | pages = 324–332 | date = March 2022 | pmid = 34664427 | doi = 10.1002/cpdd.1039 | url = }}</ref> It acts as a [[binding selectivity|selective]] [[positive allosteric modulator]] (PAM) of the [[dopamine]] [[D1 receptor|D<sub>1</sub> receptor]].<ref name="AdisInsight" /><ref name="pmid33029934" /> The drug is [[oral administration|orally active]] and crosses the [[blood–brain barrier]].<ref name="pmid33029934">{{cite journal | vauthors = Wilbraham D, Biglan KM, Svensson KA, Tsai M, Kielbasa W | title = Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects | journal = Clin Pharmacol Drug Dev | volume = 10 | issue = 4 | pages = 393–403 | date = April 2021 | pmid = 33029934 | pmc = 8048550 | doi = 10.1002/cpdd.874 | url = }}</ref> It is a [[tetrahydroisoquinoline]] and is a close [[structural analog|analogue]] of DETQ, another D<sub>1</sub> receptor PAM.<ref name="SvenssonHaoBruns2019">{{cite book | title = Advances in Pharmacology | last1 = Svensson | first1 = Kjell A. | last2 = Hao | first2 = Junliang | last3 = Bruns | first3 = Robert F. | chapter = Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders | date = 2019 | pages = 273–305 | publisher = Elsevier | issn = 1054-3589 | doi = 10.1016/bs.apha.2019.06.001 | pmid = 31378255 | url = }}</ref><ref name="pmid35175768" /><ref name="pmid33029934" /> Mevidalen has been found to produce [[wakefulness-promoting agent|wakefulness-promoting]] effects in [[sleep deprivation|sleep-deprived]] humans.<ref name="pmid34893551">{{cite journal | vauthors = McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, Biglan KM, Wafford KA | title = The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers | journal = J Pharmacol Exp Ther | volume = 380 | issue = 3 | pages = 143–152 | date = March 2022 | pmid = 34893551 | doi = 10.1124/jpet.121.000719 | url = }}</ref> [[Side effect]]s of mevidalen have been reported to include increased [[heart rate]], increased [[blood pressure]], [[insomnia]], [[dizziness]], [[nausea]], [[vomiting]], [[anxiety]], nervousness, [[fatigue (medical)|fatigue]], [[headache]]s, [[palpitation]]s, and [[contact dermatitis]], as well as [[falling (accident)|fall]]s in those with dementia.<ref name="pmid33029934" /><ref name="pmid34664427" /><ref name="pmid34893551" /> As of March 2022, mevidalen is in [[Phases of clinical research#Phase II|phase 2]] [[clinical trial]]s for the treatment of Lewy body disease.<ref name="AdisInsight" /> Besides for [[movement disorder]]s and [[dementia]], D<sub>1</sub> receptor PAMs like mevidalen might have value in the treatment of certain [[neuropsychiatric disorder]]s, such as [[depression (mood)|depression]], [[excessive somnolence]], and [[attention deficit hyperactivity disorder]].<ref name="SvenssonHaoBruns2019" />
'''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]].<ref name="AdisInsight">https://adisinsight.springer.com/drugs/800042093</ref><ref name="SvenssonHaoBruns2019" /><ref name="pmid35175768">{{cite journal | vauthors = 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 | title = Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug-Drug Interaction Risk Profile | journal = J Med Chem | volume = 65 | issue = 5 | pages = 3786–3797 | date = March 2022 | pmid = 35175768 | doi = 10.1021/acs.jmedchem.1c01887 | url = }}</ref><ref name="pmid34859493">{{cite journal | vauthors = Biglan K, Munsie L, Svensson KA, Ardayfio P, Pugh M, Sims J, Brys M | title = Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial | journal = Mov Disord | volume = 37 | issue = 3 | pages = 513–524 | date = March 2022 | pmid = 34859493 | doi = 10.1002/mds.28879 | url = }}</ref><ref name="pmid34664427">{{cite journal | vauthors = Wilbraham D, Biglan KM, Svensson KA, Tsai M, Pugh M, Ardayfio P, Kielbasa W | title = Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator, in Patients With Parkinson Disease | journal = Clin Pharmacol Drug Dev | volume = 11 | issue = 3 | pages = 324–332 | date = March 2022 | pmid = 34664427 | doi = 10.1002/cpdd.1039 | url = }}</ref> It acts as a [[binding selectivity|selective]] [[positive allosteric modulator]] (PAM) of the [[dopamine]] [[D1 receptor|D<sub>1</sub> receptor]].<ref name="AdisInsight" /><ref name="pmid33029934" /> The drug is [[oral administration|orally active]] and crosses the [[blood–brain barrier]].<ref name="pmid33029934">{{cite journal | vauthors = Wilbraham D, Biglan KM, Svensson KA, Tsai M, Kielbasa W | title = Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects | journal = Clin Pharmacol Drug Dev | volume = 10 | issue = 4 | pages = 393–403 | date = April 2021 | pmid = 33029934 | pmc = 8048550 | doi = 10.1002/cpdd.874 | url = }}</ref> It is a [[tetrahydroisoquinoline]] and is a close [[structural analog|analogue]] of DETQ, another D<sub>1</sub> receptor PAM.<ref name="SvenssonHaoBruns2019">{{cite book | title = Advances in Pharmacology | last1 = Svensson | first1 = Kjell A. | last2 = Hao | first2 = Junliang | last3 = Bruns | first3 = Robert F. | chapter = Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders | date = 2019 | pages = 273–305 | publisher = Elsevier | issn = 1054-3589 | doi = 10.1016/bs.apha.2019.06.001 | pmid = 31378255 | url = }}</ref><ref name="pmid35175768" /><ref name="pmid33029934" /> Mevidalen has been found to produce [[wakefulness-promoting agent|wakefulness-promoting]] effects in [[sleep deprivation|sleep-deprived]] humans.<ref name="pmid35110997">{{cite journal | vauthors = Jones-Tabah J, Mohammad H, Paulus EG, Clarke PBS, Hébert TE | title = The Signaling and Pharmacology of the Dopamine D1 Receptor | journal = Front Cell Neurosci | volume = 15 | issue = | pages = 806618 | date = 2021 | pmid = 35110997 | pmc = 8801442 | doi = 10.3389/fncel.2021.806618 | url = }}</ref><ref name="pmid34893551">{{cite journal | vauthors = McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, Biglan KM, Wafford KA | title = The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers | journal = J Pharmacol Exp Ther | volume = 380 | issue = 3 | pages = 143–152 | date = March 2022 | pmid = 34893551 | doi = 10.1124/jpet.121.000719 | url = }}</ref> [[Side effect]]s of mevidalen have been reported to include increased [[heart rate]], increased [[blood pressure]], [[insomnia]], [[dizziness]], [[nausea]], [[vomiting]], [[anxiety]], nervousness, [[fatigue (medical)|fatigue]], [[headache]]s, [[palpitation]]s, and [[contact dermatitis]], as well as [[falling (accident)|fall]]s in those with dementia.<ref name="pmid33029934" /><ref name="pmid34664427" /><ref name="pmid34893551" /> As of March 2022, mevidalen is in [[Phases of clinical research#Phase II|phase 2]] [[clinical trial]]s for the treatment of Lewy body disease.<ref name="AdisInsight" /> Besides for [[movement disorder]]s and [[dementia]], D<sub>1</sub> receptor PAMs like mevidalen might have value in the treatment of certain [[neuropsychiatric disorder]]s, such as [[depression (mood)|depression]], [[excessive somnolence]], and [[attention deficit hyperactivity disorder]].<ref name="SvenssonHaoBruns2019" />


==References==
==References==

Revision as of 21:46, 19 May 2022

Mevidalen
Clinical data
Other namesLY-3154207; LY3154207
Identifiers
  • 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
Chemical and physical data
FormulaC24H29Cl2NO3
Molar mass450.40 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 produce wakefulness-promoting effects in sleep-deprived humans.[7][8] Side effects of mevidalen have been reported to include increased heart rate, increased 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

  1. ^ a b c https://adisinsight.springer.com/drugs/800042093
  2. ^ a b c Svensson, Kjell A.; Hao, Junliang; Bruns, Robert F. (2019). "Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders". Advances in Pharmacology. Elsevier. pp. 273–305. doi:10.1016/bs.apha.2019.06.001. ISSN 1054-3589. PMID 31378255.
  3. ^ a b 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 (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". J Med Chem. 65 (5): 3786–3797. doi:10.1021/acs.jmedchem.1c01887. PMID 35175768.
  4. ^ 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". Mov Disord. 37 (3): 513–524. doi:10.1002/mds.28879. PMID 34859493.
  5. ^ 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". Clin Pharmacol Drug Dev. 11 (3): 324–332. doi:10.1002/cpdd.1039. PMID 34664427.
  6. ^ 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". Clin Pharmacol Drug Dev. 10 (4): 393–403. doi:10.1002/cpdd.874. PMC 8048550. PMID 33029934.
  7. ^ Jones-Tabah J, Mohammad H, Paulus EG, Clarke P, Hébert TE (2021). "The Signaling and Pharmacology of the Dopamine D1 Receptor". Front Cell Neurosci. 15: 806618. doi:10.3389/fncel.2021.806618. PMC 8801442. PMID 35110997. {{cite journal}}: Vancouver style error: initials in name 4 (help)CS1 maint: unflagged free DOI (link)
  8. ^ a b McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, Biglan KM, Wafford KA (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". J Pharmacol Exp Ther. 380 (3): 143–152. doi:10.1124/jpet.121.000719. PMID 34893551.



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