| Title : Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor - Salovich_2012_Bioorg.Med.Chem.Lett_22_5084 |
| Author(s) : Salovich JM , Vinson PN , Sheffler DJ , Lamsal A , Utley TJ , Blobaum AL , Bridges TM , Le U , Jones CK , Wood MR , Daniels JS , Conn PJ , Niswender CM , Lindsley CW , Hopkins CR |
| Ref : Bioorganic & Medicinal Chemistry Lett , 22 :5084 , 2012 |
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Abstract :
Herein we describe the discovery and development of a novel class of M(4) positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC(50)=1.3 muM) and excellent efficacy as noted by the 14.6-fold leftward shift of the agonist concentration-response curve. ML293 was also selective versus the other muscarinic subtypes and displayed excellent in vivo PK properties in rat with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1h, [Brain]=10.3 muM, B:P=0.85). |
| PubMedSearch : Salovich_2012_Bioorg.Med.Chem.Lett_22_5084 |
| PubMedID: 22738637 |
Salovich JM, Vinson PN, Sheffler DJ, Lamsal A, Utley TJ, Blobaum AL, Bridges TM, Le U, Jones CK, Wood MR, Daniels JS, Conn PJ, Niswender CM, Lindsley CW, Hopkins CR (2012)
Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor
Bioorganic & Medicinal Chemistry Lett
22 :5084
Salovich JM, Vinson PN, Sheffler DJ, Lamsal A, Utley TJ, Blobaum AL, Bridges TM, Le U, Jones CK, Wood MR, Daniels JS, Conn PJ, Niswender CM, Lindsley CW, Hopkins CR (2012)
Bioorganic & Medicinal Chemistry Lett
22 :5084