Heterocyclic fused pyridone carboxylic acid M 1 positive allosteric modulators Scott D. Kuduk a, * , Christina N. Di Marco a , Ronald K. Chang a , William J. Ray b , Lei Ma b , Marion Wittmann b , Matthew A. Seager b , Kenneth A. Koeplinger c , Charles D. Thompson c , George D. Hartman a , Mark T. Bilodeau a a Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA b Department of Alzheimer’s Research, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA c Department of Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA article info Article history: Received 4 February 2010 Revised 24 February 2010 Accepted 25 February 2010 Available online 3 March 2010 Keywords: M 1 Muscarinic Quinolone Allosteric Alzheimer’s abstract The phenyl ring in a series of quinolone carboxylic acid M 1 positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure. Ó 2010 Published by Elsevier Ltd. Cholinergic neurons serve essential functions in both the peripheral and central nervous systems (CNS). Acetylcholine is the principal neurotransmitter targeting nicotinic and muscarinic metabotropic receptors. Muscarinic receptors are class A G-protein coupled receptors (GPCR) widely expressed in the CNS. There are five muscarinic sub-types, designated M 1 –M 5 , 1,2 of which M 1 is most highly expressed in the hippocampus, striatum, and cortex, 3 implying it may play a central role in memory and higher brain function. A common observation in Alzheimer’s disease (AD) is the pro- gressive degeneration of cholinergic neurons in the basal forebrain leading to cognitive decline. 4 One approach to treat these cognitive symptoms of AD would be the direct activation of the M 1 receptor. 5 In this regard, a number of non-selective M 1 agonists have shown potential to improve cognitive performance in AD patients, but were clinically limited by cholinergic side effects thought to be the result of activation of other muscarinic sub-types via binding to the highly conserved orthosteric acetylcholine binding site. 6,7 One conduit to stimulate selectively for M 1 over the other sub- types is to target allosteric sites on M 1 that are less highly con- served than the orthosteric site. 8,9 It was recently reported that quinolone carboxylic acid 1 is a selective positive allosteric modu- lator of the M 1 receptor with excellent selectivity for this sub- type. 10,11 Endeavors to improve the potency of 1 led to the identification of biaryl replacements for the para-methoxybenzyl group such as biphenyl 2 (Fig. 1). 12 While these compounds were improved in terms of in vitro activity, higher plasma protein bind- ing led to decreased CNS exposure impeding further in vivo evalu- ation. Previous SAR efforts on the A-ring showed substitution was not tolerated, with the exception of fluorination at the 5- and 8- positions. This Letter, describes efforts to identify heterocyclic fused A-rings that would retain M 1 potency, reduce protein bind- ing, and improve CNS exposure. The chemistry used to prepare test compounds is shown in Scheme 1. The appropriate heterocyclic acid chloride 3 is treated with potassium 3-(ethoxy)-3-oxopropanoate and MgCl 2 to pro- 0960-894X/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.bmcl.2010.02.096 * Corresponding author. E-mail address: scott_d_kuduk@merck.com (S.D. Kuduk). N O O OH N O O OH OMe 2: M 1 IP = 212 nM -Higher protein binding -Reduced CNS exposure 1: M 1 IP = 660 nM PB = 96-98% B C A 5 8 Figure 1. Bioorganic & Medicinal Chemistry Letters 20 (2010) 2533–2537 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl