Discovery, Synthesis, and Structure–Activity Relationship Development of a Series of N-4-(2,5-Dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4) with Oral Efficacy in an Antiparkinsonian Animal Model

• Published in: Journal of medicinal chemistry Vol. 54; no. 21; pp. 7639 - 7647
• Main Authors: Jones, Carrie K, Engers, Darren W, Thompson, Analisa D, Field, Julie R, Blobaum, Anna L, Lindsley, Stacey R, Zhou, Ya, Gogliotti, Rocco D, Jadhav, Satyawan, Zamorano, Rocio, Bogenpohl, Jim, Smith, Yoland, Morrison, Ryan, Daniels, J. Scott, Weaver, C. David, Conn, P. Jeffrey, Lindsley, Craig W, Niswender, Colleen M, Hopkins, Corey R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.11.2011; Amer Chemical Soc
• Subjects: Administration, Oral; Allosteric Regulation; Animals; Antiparkinson Agents - chemical synthesis; Antiparkinson Agents - pharmacokinetics; Antiparkinson Agents - pharmacology; Biological Availability; Catalepsy - chemically induced; Catalepsy - drug therapy; Chemistry, Medicinal; CHO Cells; Cricetinae; Cricetulus; Haloperidol; Humans; In Vitro Techniques; Isoindoles - chemical synthesis; Isoindoles - pharmacokinetics; Isoindoles - pharmacology; Life Sciences & Biomedicine; Microsomes, Liver - metabolism; Pharmacology & Pharmacy; Picolinic Acids - chemical synthesis; Picolinic Acids - pharmacokinetics; Picolinic Acids - pharmacology; Rats; Receptors, Metabotropic Glutamate - physiology; Science & Technology; Structure-Activity Relationship; DOPAMINE; MGLUR4; PHARMACOLOGY; PARKINSONS-DISEASE; LEVODOPA
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200956q

There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood–brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)­phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.