Discovery of a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide M4 positive allosteric modulator (PAM) chemotype |
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| Institution: | 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA;2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;3. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA;4. Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;5. Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA;1. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28871-Alcalá de Henares, Madrid, Spain;2. CAI Cartografía Cerebral, Instituto Pluridisciplinar UCM, Paseo Juan XXIII, 1, Madrid 28040, Spain;3. Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain;4. Departamento de Neurobiología Molecular, Celular y del Desarrollo, Instituto Cajal, Avda. Doctor Arce, 37, Madrid 28002, Spain;5. Instituto Tecnológico PET, Calle Manuel Bartolomé Cossío, 10, Madrid 28040, Spain;1. College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, United States;2. Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland;3. University of Basel, CH-4003 Basel, Switzerland;4. Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, United States;5. Department of Biochemistry, Vanderbilt University, 2200 Pierce Ave., Nashville, TN, United States;6. Department of Biology, University of Nebraska at Omaha, Omaha, NE, United States;1. Department of Civil and Mechanical Engineering, University of Cassino and Southern Lazio, Via G. Di Biasio 43, 03043 Cassino, Italy;2. Link Campus University, via del Casale di San Pio V 44, 00165 Rome, Italy;3. Department of Civil Engineering, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy |
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| Abstract: | This Letter details our efforts to discover structurally unique M4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1H-benzod]1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo1,2-a]pyrazine-6-carboxamide core that provided improved M4 PAM activity and CNS penetration. |
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| Keywords: | Muscarinic acetylcholine receptor Positive allosteric modulator (PAM) Structure activity relationship (SAR) |
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