Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects

Journal of Medicinal Chemistry

Volumn 59, Issue 13, 2016, Pages 6313-6328

  Davoren, Jennifer E ^a   Lee, Che Wah ^a   Garnsey, Michelle ^a   Brodney, Michael A ^a   Cordes, Jason ^a   Dlugolenski, Keith ^a   Edgerton, Jeremy R ^a   Harris, Anthony R ^a   Helal, Christopher J ^a   Jenkinson, Stephen ^a   Kauffman, Gregory W ^a   Kenakin, Terrence P ^b   Lazzaro, John T ^a   Lotarski, Susan M ^a   Mao, Yuxia ^a   Nason, Deane M ^a   Northcott, Carrie ^a   Nottebaum, Lisa ^a   O'Neil, Steven V ^a   Pettersen, Betty ^a   Popiolek, Michael ^a   Reinhart, Veronica ^a   Salomon Ferrer, Romelia ^a   Steyn, Stefanus J ^a   Webb, Damien ^a   Zhang, Lei ^a   Grimwood, Sarah ^a   more..

^a PFIZER INC   (United States)

^b UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 HYDROXYTETRAHYDRO 2H PYRAN 4 YL] 5 METHYL 4 [4 (1,3 THIAZOL 4YL)BENZYL]PYRIDINE 2 CARBOXAMIDE; 4 (4 (1H PYRAZOL 1 YL)BENZYL) N 2 HYDROXYCYCLOHEXYL) 5 METHYLPICOLINAMIDE; 4 (4 (1H PYRAZOL 1 YL)BENZYL) N 3 HYDROXYTETRAHYDRO 2H PYRAN 4 YL) 5 METHYLPICOLINAMIDE; ETHYL 5 METHYL 4 (4,4,5,5 TETRAMETHYL 1,3,2 DIOXABOROLAN 2YL)PYRIDINE 2 CARBOXYLATE; MUSCARINIC M1 RECEPTOR AGONIST; N (3 HYDROXYTETRAHYDRO 2H PYRAN 4 YL) 5 METHYL 4 (4 (OXAZOL 4 YL)BENZYL)PICOLINAMIDE; N (3 HYDROXYTETRAHYDRO 2H PYRAN 4 YL) 5 METHYL 4 (4 (THIAZOL 4 YL)BENZYL)PICOLINAMIDE; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG; MUSCARINIC M1 RECEPTOR; N-(3-HYDROXYTETRAHYDRO-2H-PYRAN-4-YL)-5-METHYL-4-(4-(1,3-THIAZOL-4-YL)BENZYL)PYRIDINE-2-CARBOXAMIDE; PICOLINIC ACID DERIVATIVE; THIAZOLE DERIVATIVE;

ALZHEIMER DISEASE; AMIDATION; AREA UNDER THE CURVE; ARTICLE; BLOOD BRAIN BARRIER; CHOLINERGIC ACTIVITY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG EFFECT; DRUG HYDROLYSIS; DRUG PENETRATION; DRUG SAFETY; EC50; FEMALE; HUMAN; MALE; MAXIMUM PLASMA CONCENTRATION; PHARMACOPHORE; PHYSICAL CHEMISTRY; PROTON NUCLEAR MAGNETIC RESONANCE; SCHIZOPHRENIA; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION; AGONISTS; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; METABOLISM; MOLECULAR MODEL; MOUSE; RAT; SYNTHESIS;

ANIMALS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; FEMALE; MALE; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PICOLINIC ACIDS; RATS; RECEPTOR, MUSCARINIC M1; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 84978634494     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00544     Document Type: Article

References (114)

1. Shirey, J. K.; Brady, A. E.; Jones, P. J.; Davis, A. A.; Bridges, T. M.; Kennedy, J. P.; Jadhav, S. B.; Menon, U. N.; Xiang, Z.; Watson, M. L.; Christian, E. P.; Doherty, J. J.; Quirk, M. C.; Snyder, D. H.; Lah, J. J.; Levey, A. I.; Nicolle, M. M.; Lindsley, C. W.; Conn, P. J. A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning J. Neurosci. 2009, 29, 14271-14286 10.1523/JNEUROSCI.3930-09.2009
2. Felder, C. C.; Bymaster, F. P.; Ward, J.; DeLapp, N. Therapeutic opportunities for muscarinic receptors in the central nervous system J. Med. Chem. 2000, 43, 4333-4353 10.1021/jm990607u
3. Ghoshal, A.; Rook, J. M.; Dickerson, J. W.; Roop, G. N.; Morrison, R. D.; Jalan-Sakrikar, N.; Lamsal, A.; Noetzel, M. J.; Poslusney, M. S.; Wood, M. R.; Melancon, B. J.; Stauffer, S. R.; Xiang, Z.; Daniels, J. S.; Niswender, C. M.; Jones, C. K.; Lindsley, C. W.; Conn, P. J. Potentiation of M1 muscarinic receptor reverses plasticity deficits and negative and cognitive symptoms in a schizophrenia mouse model Neuropsychopharmacology 2016, 41, 598-610 10.1038/npp.2015.189
4. Foster, D. J.; Choi, D. L.; Conn, P. J.; Rook, J. M. Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia Neuropsychiatr. Dis. Treat. 2014, 10, 183-191 10.2147/NDT.S55104
5. Korczyn, A. D. Muscarinic M(1) agonists in the treatment of Alzheimer's disease Expert Opin. Invest. Drugs 2000, 9, 2259-2267 10.1517/13543784.9.10.2259
6. Kruse, A. C.; Ring, A. M.; Manglik, A.; Hu, J.; Hu, K.; Eitel, K.; Hubner, H.; Pardon, E.; Valant, C.; Sexton, P. M.; Christopoulos, A.; Felder, C. C.; Gmeiner, P.; Steyaert, J.; Weis, W. I.; Garcia, K. C.; Wess, J.; Kobilka, B. K. Activation and allosteric modulation of a muscarinic acetylcholine receptor Nature 2013, 504, 101-106 10.1038/nature12735
7. http://www.heptares.com/news/261/74/Heptares-Announces-Positive-Results-from-Phase-1b-Clinical-Trial-with-HTL9936-a-First-In-Class-Selective-Muscarinic-M1-Receptor-Agonist-for-Improving-Cognition-in-Dementia-and-Schizophrenia.html (accessed February 12, 2016).
8. 1 muscarinic acetylcholine receptor achieved by allosteric potentiation Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 15950-15955 10.1073/pnas.0900903106
9. Kuduk, S. D.; Chang, R. K.; Di Marco, C. N.; Pitts, D. R.; Greshock, T. J.; Ma, L.; Wittmann, M.; Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M. T.; Ray, W. J. Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold J. Med. Chem. 2011, 54, 4773-4780 10.1021/jm200400m
10. 1 muscarinic acetylcholine receptor J. Biol. Chem. 2014, 289, 33701-33711 10.1074/jbc.M114.604967
11. Vardigan, J. D.; Cannon, C. E.; Puri, V.; Dancho, M.; Koser, A.; Wittmann, M.; Kuduk, S. D.; Renger, J. J.; Uslaner, J. M. Improved cognition without adverse effects: novel M1 muscarinic potentiator compares favorably to donepezil and xanomeline in rhesus monkey Psychopharmacology (Berl) 2015, 232, 1859-1866 10.1007/s00213-014-3813-x
12. Uslaner, J. M.; Eddins, D.; Puri, V.; Cannon, C. E.; Sutcliffe, J.; Chew, C. S.; Pearson, M.; Vivian, J. A.; Chang, R. K.; Ray, W. J.; Kuduk, S. D.; Wittmann, M. The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque Psychopharmacology 2013, 225, 21-30 10.1007/s00213-012-2788-8
13. Lange, H. S.; Cannon, C. E.; Drott, J. T.; Kuduk, S. D.; Uslaner, J. M. The M1 muscarinic positive allosteric modulator PQCA improves performance on translatable tests of memory and attention in rhesus monkeys J. Pharmacol. Exp. Ther. 2015, 355, 442-450 10.1124/jpet.115.226712
14. Kuduk, S. D.; Beshore, D. C. SAR studies on carboxylic acid series M(1) selective positive allosteric modulators (PAMs) Curr. Top. Med. Chem. 2014, 14, 1738-1754 10.2174/1568026614666140826120224
15. Kuduk, S. D.; Chang, R. K.; Greshock, T. J.; Ray, W. J.; Ma, L.; Wittmann, M.; Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M. T. Identification of amides as carboxylic Acid surrogates for quinolizidinone-based M1 positive allosteric modulators ACS Med. Chem. Lett. 2012, 3, 1070-1074 10.1021/ml300280g
16. Kuduk, S. D.; Di Marco, C. N.; Saffold, J. R.; Ray, W. J.; Ma, L.; Wittmann, M.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M. T.; Beshore, D. C. Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators Bioorg. Med. Chem. Lett. 2014, 24, 1417-1420 10.1016/j.bmcl.2014.01.012
17. Yang, Z. Q.; Shu, Y.; Ma, L.; Wittmann, M.; Ray, W. J.; Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M. T.; Kuduk, S. D. Discovery of naphthyl-fused 5-membered lactams as a new class of m1 positive allosteric modulators ACS Med. Chem. Lett. 2014, 5, 604-608 10.1021/ml500055h
18. Kuduk, S. D.; Chang, R. K.; Di Marco, C. N.; Ray, W. J.; Ma, L.; Wittmann, M.; Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M. T. Quinolizidinone carboxylic acids as CNS penetrant, selective m1 allosteric muscarinic receptor modulators ACS Med. Chem. Lett. 2010, 1, 263-267 10.1021/ml100095k
19. Kuduk, S. D.; Di Marco, C. N.; Cofre, V.; Pitts, D. R.; Ray, W. J.; Ma, L.; Wittmann, M.; Veng, L.; Seager, M. A.; Koeplinger, K.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M. T. N-heterocyclic derived M1 positive allosteric modulators Bioorg. Med. Chem. Lett. 2010, 20, 1334-1337 10.1016/j.bmcl.2010.01.013
20. Kuduk, S. D.; Chang, R. K.; Di Marco, C. N.; Ray, W. J.; Ma, L.; Wittmann, M.; Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M. T. Quinolizidinone carboxylic acid selective M1 allosteric modulators: SAR in the piperidine series Bioorg. Med. Chem. Lett. 2011, 21, 1710-1715 10.1016/j.bmcl.2011.01.094
21. Kuduk, S. D.; Di Marco, C. N.; Cofre, V.; Ray, W. J.; Ma, L.; Wittmann, M.; Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.; Hartman, G. D.; Bilodeau, M. T. Fused heterocyclic M1 positive allosteric modulators Bioorg. Med. Chem. Lett. 2011, 21, 2769-2772 10.1016/j.bmcl.2010.10.028
22. Kuduk, S. D.; Dimarco, C. N.; Yang, Z.-Q. N-linked quinolineamide M1 receptor positive allosteric modulators. WO 2012158474, May 11, 2012.
23. Kuduk, S. D.; Di Marco, C. N.; Greshock, T. J. N-methyl-tetrahydroquinoline M1 receptor positive allosteric modulators. WO 2012158473, May 11, 2012.
24. Kuduk, S. D.; Chang, R. K.; Greshock, T. J. Dihydrobenzoquinazolinone M1 receptor positive allosteric modulators. WO 2012047702, September 29, 2011.
25. Kuduk, S. D.; Beshore, D. C.; Yang, Z.-Q.; Shu, Y.; Pitts, D. Preparation of benzoisoindolylmethyllactam derivatives and analogs for use as M1 receptor positive allosteric modulators. WO 2012158475, May 11, 2012.
26. Kuduk, S. D.; Beshore, D. C.; Yang, Z.; Shu, Y. Fused isoindolone M1 receptor positive allosteric modulators and their preparation and use for the treatment of M1-mediated diseases. WO 2012003147, June 27, 2011.
27. Kuduk, S. D.; Skudlarek, J. W. Preparation of heterocyclic fused phenanthrolinones as M1 receptor positive allosteric modulators for the treatment of diseases mediated by the M1 receptor. WO 2011159553, June 10, 2011.
28. Kuduk, S. D.; Schlegel, K.-A.; Yang, Z.-Q. Quinoline-amide derivatives as M1 receptor positive allosteric modulators and their preparation, pharmaceutical compositions and use in the treatment of diseases. WO 2011084368, December 13, 2010.
29. Kuduk, S. D.; Gilbert, K. F. Preparation of tetrahydroquinolinylamide derivatives for use as M1 receptor positive allosteric modulators. WO 2011159554, June 10, 2011.
30. Kuduk, S. D.; Chang, R. K.; Greshock, T. J. Benzoquinazolinone derivatives as M1 receptor positive allosteric modulators and their preparation, pharmaceutical compositions and use in the treatment of diseases. WO 2011025851, August 26, 2010.
31. Kuduk, S. D.; Chang, R. K.; Greshock, T. J. Quinolizine-3-carboxamide derivatives as M1 receptor positive allosteric modulators and their preparation and for the treatment of diseases. WO 2011062853, November 15, 2010.
32. Kuduk, S. D.; Chang, R. K.; Greshock, T. J. Pyridoquinazolinone as M1 receptor positive allosteric modulators and their preparation, pharmaceutical compositions and use in the treatment of diseases. WO 2011075371, December 9, 2010.
33. Kuduk, S. D.; Beshore, D. C.; Dimarco, C. N.; Greshock, T. J. Aminobenzoquinazolinone M1 receptor positive allosteric modulators. WO 2011084371, December 13, 2010.
34. Beshore, D. C.; Kuduk, S. D.; Dipardo, R. M. Pyrazoloquinolinone derivatives as M1 receptor positive allosteric modulators and their preparation and use for the treatment of M1 receptor-mediated diseases. WO 2011049731, October 1, 2010.
35. Beshore, D. C.; Kuduk, S. D. Heterocyclic-fused pyrazolo[4,3-c]pyridin-3-one M1 receptor positive allosteric modulators. WO 2011041143, September 20, 2010.
36. Beshore, D. C.; Kuduk, S. D. Heterocyclic quinolizine derived M1 receptor positive allosteric modulators. WO 2011137049, April 25, 2011.
37. Beshore, D. C.; Dimarco, C. N.; Kuduk, S. D. Naphthalene carboxamide muscarinic M1 receptor positive allosteric modulators. WO 2011149801, May 23, 2011.
38. Kuduk, S. D.; Di Marco, C. N. Preparation of 1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylates as M1 receptor positive allosteric modulators. WO 2009094279, July 31, 2009.
39. Kuduk, S. D.; Di Marco, C. N. Preparation of quinolizidinone M1 receptor positive allosteric modulators. WO 2010042347, September 29, 2009.
40. Kuduk, S. D.; Di Marco, C. N. Preparation of fused heterocyclic M1 receptor positive allosteric modulators. WO 2010047990, October 13, 2009.
41. Beshore, D. C.; Kuduk, S. D. Pyrazolo[4,3-c]cinnolin-3-one derivatives as M1 receptor positive allosteric modulators and their preparation, pharmaceutical compositions and use in the treatment of diseases. WO 2010096338, February 12, 2010.
42. Beshore, D. C.; Kuduk, S. D. Preparation of fused pyrazolopyridazines as muscarinic M1 receptor positive allosteric modulators. WO 2010123716, April 13, 2010.
43. Kuduk, S. D.; Di Marco, C. N.; Shipe, W. D. Preparation of oxodihydroquinoline derivatives for use as M1 receptor positive allosteric modulators. WO 2009134668, April 23, 2009.
44. Kuduk, S. D.; Chang, R. K.; Di Marco, C. N. Quinolizidinone M1 receptor positive allosteric modulators. WO 2009102574, February 3, 2009.
45. Kuduk, S. D.; Chang, R. K.; Di Marco, C. N. Preparation of quinolizidinone M1 receptor positive allosteric modulators. WO 2009117283, March 11, 2009.
46. Kuduk, S. D.; Chang, R. K. Synthesis of quinolizidinone M1 receptor positive allosteric modulators. WO 2009051715, October 15, 2008.
47. Kuduk, S. D.; Chang, R. K. Preparation of heterocyclylmethyl oxoquinolizinecarboxylates as muscarinic M1 receptor positive allosteric modulators. WO 2009094279, January 15, 2009.
48. Beshore, D. C.; Dipardo, R. M.; Kuduk, S. D. Preparation of fused pyridone M1 receptor positive allosteric modulators. WO 2009102588, February 4, 2009.
49. Lindsley, C.; Shipe, W. D.; Yang, F.; Bunda, J. L. Preparation of benzyl-substituted quinolone M1 receptor positive allosteric modulators. WO 2008002621, June 27, 2007.
50. Shipe, W. D.; Lindsley, C.; Hallett, D. Quinolone derivatives, processes for preparing them, pharmaceutical compositions containing them, and their use as M1 receptor positive allosteric modulators. WO 2007067489, December 4, 2006.
51. Shipe, W. D.; Lindsley, C.; Hallett, D. Preparation of quinolone M1 receptor positive allosteric modulators. WO 2007100366, December 4, 2006.
52. Kuduk, S. D.; Beshore, D. C.; Di Marco, C. N.; Greshock, T. J. Benzoquinazolinone derivatives as M1 receptor positive allosteric modulators and their preparation, pharmaceutical compositions and use in the treatment of diseases. WO 2010059773, May 27, 2010.
53. Yamada, M.; Suzuki, S.; Sugimoto, T.; Nakamura, M.; Sakamoto, H.; Kamata, M. Isoindolin-1-one derivatives as cholinergic muscarinic M1 receptor positive allosteric modulators and their preparation and use for the treatment of diseases. WO 2015163485 April 22, 2015.
54. Payne, A.; Castro Pineiro, J. L.; Birch, L. M.; Khan, A.; Braunton, A. J.; Kitulagoda, J. E.; Soejima, M. Preparation of 4-azaindole derivatives as muscarinic M1 receptor modulators for treatment of cognitive deficits. US 20150094328, September 30, 2014.
55. Ogino, M.; Kimura, E.; Suzuki, S.; Ashizawa, T.; Imaeda, T.; Fujimori, I.; Arai, R. Preparation of nitrogen-containing heterocyclic compound as muscarinic M1 receptor positive allosteric modulators for treatment of nervous system disease. WO 2015190564, June 11, 2015.
56. Lindsley, C. W.; Conn, P. J.; Stauffer, S. R.; Panarese, J. D. Preparation of benzyldihydrobenzooxazinecarboxamide derivatives for use as positive allosteric modulators of muscarinic acetylcholine receptor M1. WO 2015080904, November 18, 2014.
57. Groebke Zbinden, K.; Pinard, E.; Ryckmans, T. Preparation of fluoro-naphthyl derivatives as muscarinic M1 receptor positive allosteric modulators. WO 2015110370, January 19, 2015.
58. Ballard, T. M.; Groebke Zbinden, K.; Pinard, E.; Ryckmans, T.; Schaffhauser, H. Preparation of indole and indazole derivatives as muscarinic M1 receptor pos. allosteric modulators. WO 2015044072, September 22, 2014.
59. Ballard, T. M.; Flohr, A.; Groebke Zbinden, K.; Pinard, E.; Ryckmans, T.; Schaffhauser, H. Preparation of pyrrolopyridine and pyrazolopyridine derivatives as muscarinic M1 receptor modulators. WO 2015028483, August 8, 2014.
60. Sugimoto, T.; Nakamura, M.; Sakamoto, H.; Suzuki, S.; Yamada, M.; Kamata, M.; Kojima, T.; Fujimori, I.; Shimokawa, K. Preparation of nitrogen-containing heterocyclic compounds as muscarinic M1 receptor positive allosteric modulators. WO 2014077401, November 18, 2013.
61. Lindsley, C. W.; Conn, P. J.; Stauffer, S. R.; Panarese, J. D. Substituted 1-benzylquinoxalin-2(1H)-one analogs as positive allosteric modulators of muscarinic acetylcholine receptor M1. WO 2014179226, April 28, 2014.
62. Lindsley, C. W.; Conn, P. J.; Stauffer, S. R.; Panarese, J. D. Quinazolinone and pyridopyrimidinone derivatives as positive allosteric modulators of muscarinic acetylcholine receptor M1 and their preparation and use for the treatment of neurological and psychiatric disorders. WO 2014179237, April 28, 2014.
63. Davie, B. J.; Valant, C.; White, J. M.; Sexton, P. M.; Capuano, B.; Christopoulos, A.; Scammells, P. J. Synthesis and pharmacological evaluation of analogues of Benzyl Quinolone Carboxylic Acid (BQCA) designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor J. Med. Chem. 2014, 57, 5405-5418 10.1021/jm500556a
64. Swinnen, D.; Montagne, C.; Pomel, V.; Quattropani, A.; Molette, J.; Gerber, P. Tetraaza-cyclopenta[a]indenyl derivatives as M1 receptor positive allosteric modulators useful in the treatment of diseases mediated by the muscarinic M1 mediator and their preparation. WO 2013091773, November 30, 2012.
65. Sakamoto, H.; Sugimoto, T. Preparation of heterocyclic compounds as cholinergic muscarinic M1 receptor positive allosteric modulators. WO 2013129622, February 28, 2013.
66. Lindsley, C. W.; Conn, P. J.; Wood, M. R.; Melancon, B. J.; Poslusney, M. S.; Tarr, J. C. Substituted pyrazol-benzyl analogues as positive allosteric modulators of mAChR M1 receptors. WO 2013106795, January 12, 2013.
67. Lindsley, C. W.; Conn, P. J.; Wood, M. R.; Hopkins, C. R.; Melancon, B. J.; Poslusney, M. S.; Engers, D. W. Substituted 2-(4-heterocyclylbenzyl)isoindolin-1-one analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M1. WO 2013063549, October 28, 2012.
68. Lindsley, C. W.; Conn, P. J.; Wood, M. R.; Hopkins, C. R.; Melancon, B. J.; Poslusney, M. S. Preparation of substituted benzylspiroindolin-2-one derivatives as positive allosteric modulators of mAChR M1 receptor. WO 2013071201, November 10, 2012.
69. Lindsley, C. W.; Conn, P. J.; Wood, M. R.; Tarr, J. C.; Bridges, T. M. Indole compounds as positive allosteric modulators of the muscarinic receptor. WO 2011163280, June 21, 2011.
70. Reid, P. R.; Bridges, T. M.; Sheffler, D. J.; Cho, H. P.; Lewis, L. M.; Days, E.; Daniels, J. S.; Jones, C. K.; Niswender, C. M.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W.; Wood, M. R. Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): The development of ML169, an MLPCN probe Bioorg. Med. Chem. Lett. 2011, 21, 2697-2701 10.1016/j.bmcl.2010.12.015
71. Tarr, J. C.; Turlington, M. L.; Reid, P. R.; Utley, T. J.; Sheffler, D. J.; Cho, H. P.; Klar, R.; Pancani, T.; Klein, M. T.; Bridges, T. M.; Morrison, R. D.; Blobaum, A. L.; Xiang, Z.; Daniels, J. S.; Niswender, C. M.; Conn, P. J.; Wood, M. R.; Lindsley, C. W. Targeting selective activation of M(1) for the treatment of Alzheimer's disease: further chemical optimization and pharmacological characterization of the M(1) positive allosteric modulator ML169 ACS Chem. Neurosci. 2012, 3, 884-895 10.1021/cn300068s
72. Mistry, S. N.; Valant, C.; Sexton, P. M.; Capuano, B.; Christopoulos, A.; Scammells, P. J. Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M1 muscarinic receptor J. Med. Chem. 2013, 56, 5151-5172 10.1021/jm400540b
73. Davie, B. J.; Sexton, P. M.; Capuano, B.; Christopoulos, A.; Scammells, P. J. Development of a photoactivatable allosteric ligand for the M1 muscarinic acetylcholine receptor ACS Chem. Neurosci. 2014, 5, 902-907 10.1021/cn500173x
74. Quattropani, A.; Kulkarni, S. S.; Murugesan, K.; Banerjee, J. Preparation of tetraaza-cyclopenta[a]indenyl derivatives as muscarinic M1 mediators. WO 2014198808 Dec 18, 2014.
75. Sugimoto, T.; Shimokawa, K.; Kojima, T.; Sakamoto, H.; Fujimori, I.; Nakamura, M.; Yamada, M.; Murakami, M.; Kamata, M.; Suzuki, S. Nitrogen-containing heterocyclic compounds and their use for pharmaceuticals and cholinergic muscarinic M1 receptor positive allosteric modulation. WO 2015174534 Nov 19, 2015.
76. Davoren, J. E.; O'Neil, S. V.; Anderson, D. P.; Brodney, M. A.; Chenard, L.; Dlugolenski, K.; Edgerton, J. R.; Green, M.; Garnsey, M.; Grimwood, S.; Harris, A. R.; Kauffman, G. W.; LaChapelle, E.; Lazzaro, J. T.; Lee, C.-W.; Lotarski, S. M.; Nason, D. M.; Obach, R. S.; Reinhart, V.; Salomon-Ferrer, R.; Steyn, S. J.; Webb, D.; Yan, J.; Zhang, L. Design and optimization of selective azaindole amide M1 positive allosteric modulators Bioorg. Med. Chem. Lett. 2016, 26, 650-655 10.1016/j.bmcl.2015.11.053
77. Mistry, S. N.; Jorg, M.; Lim, H.; Vinh, N. B.; Sexton, P. M.; Capuano, B.; Christopoulos, A.; Lane, J. R.; Scammells, P. J. 4-Phenylpyridin-2-one derivatives: A novel class of positive allosteric modulator of the M1 muscarinic acetylcholine receptor J. Med. Chem. 2016, 59, 388-409 10.1021/acs.jmedchem.5b01562
78. Davoren, J. E.; O'Neil, S. V.; Anderson, D. P.; Brodney, M. A.; Chenard, L.; Dlugolenski, K.; Edgerton, J. R.; Green, M.; Garnsey, M.; Grimwood, S.; Harris, A. R.; Kauffman, G. W.; LaChapelle, E.; Lazzaro, J. T.; Lee, C. W.; Lotarski, S. M.; Nason, D. M.; Obach, R. S.; Reinhart, V.; Salomon-Ferrer, R.; Steyn, S. J.; Webb, D.; Yan, J.; Zhang, L. Design and optimization of selective azaindole amide M1 positive allosteric modulators Bioorg. Med. Chem. Lett. 2016, 26, 650-655 10.1016/j.bmcl.2015.11.053
79. Mistry, S. N.; Lim, H.; Jorg, M.; Capuano, B.; Christopoulos, A.; Lane, J. R.; Scammells, P. J. Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M Muscarinic Acetylcholine Receptor ACS Chem. Neurosci. 2016, 7, 647-661 10.1021/acschemneuro.6b00018
80. Brodney, M. A.; Davoren, J. E.; Garnsey, M. R.; Zhang, L.; O'Neil, S. V. Pyridine derivatives as muscarinic m1 receptor positive allosteric modulators. WO 2016009297, July 2, 2015.
81. Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties ACS Chem. Neurosci. 2010, 1, 435-449 10.1021/cn100008c
82. Li, J.; Grillo, A. S.; Burke, M. D. From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks Acc. Chem. Res. 2015, 48, 2297-2307 10.1021/acs.accounts.5b00128
83. Gillis, E. P.; Burke, M. D. Iterative Cross-Couplng with MIDA Boronates: Towards a General Platform for Small Molecule Synthesis Aldrichim. Acta 2009, 42, 17-27
84. The exemplified THP ring has been highlighted in multiple Merck patents. For a recent relevant example see the following: Kuduk, S. D.; Gilbert, K. F. Tetrahydroquinoline amide m1 receptor positive allosteric modulators. WO 2011159554, 2011.
85. Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.; Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis Bioorg. Med. Chem. Lett. 2009, 19, 4406-4409 10.1016/j.bmcl.2009.05.062
86. Feng, B.; Mills, J. B.; Davidson, R. E.; Mireles, R. J.; Janiszewski, J. S.; Troutman, M. D.; de Morais, S. M. In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system Drug. Metab. Dispos. 2008, 36, 268-275 10.1124/dmd.107.017434
87. Reichel, A. The role of blood-brain barrier studies in the pharmaceutical industry Curr. Drug Metab. 2006, 7, 183-203 10.2174/138920006775541525
88. Lombardo, F.; Shalaeva, M. Y.; Tupper, K. A.; Gao, F. ElogD(oct): a tool for lipophilicity determination in drug discovery. 2. Basic and neutral compounds J. Med. Chem. 2001, 44, 2490-2497 10.1021/jm0100990
89. Di, L.; Whitney-Pickett, C.; Umland, J. P.; Zhang, H.; Zhang, X.; Gebhard, D. F.; Lai, Y.; Federico, J. J., 3rd; Davidson, R. E.; Smith, R.; Reyner, E. L.; Lee, C.; Feng, B.; Rotter, C.; Varma, M. V.; Kempshall, S.; Fenner, K.; El-Kattan, A. F.; Liston, T. E.; Troutman, M. D. Development of a new permeability assay using low-efflux MDCKII cells J. Pharm. Sci. 2011, 100, 4974-4985 10.1002/jps.22674
90. Johnson, T. W.; Dress, K. R.; Edwards, M. Using the Golden Triangle to optimize clearance and oral absorption Bioorg. Med. Chem. Lett. 2009, 19, 5560-5564 10.1016/j.bmcl.2009.08.045
91. Independent to our own research efforts Takeda published a patent on a set of compounds containing a similarly substituted pyridine ring. See the following: Ogino, M.; Kimura, E.; Suzuki, S.; Ashizawa, T.; Imaeda, T.; Fujimori, I.; Arai, R. Nitrogen-containing heterocyclic compound. WO2015190564, 2015.
92. Johnson, T. W.; Richardson, P. F.; Bailey, S.; Brooun, A.; Burke, B. J.; Collins, M. R.; Cui, J. J.; Deal, J. G.; Deng, Y. L.; Dinh, D.; Engstrom, L. D.; He, M.; Hoffman, J.; Hoffman, R. L.; Huang, Q.; Kania, R. S.; Kath, J. C.; Lam, H.; Lam, J. L.; Le, P. T.; Lingardo, L.; Liu, W.; McTigue, M.; Palmer, C. L.; Sach, N. W.; Smeal, T.; Smith, G. L.; Stewart, A. E.; Timofeevski, S.; Zhu, H.; Zhu, J.; Zou, H. Y.; Edwards, M. P. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations J. Med. Chem. 2014, 57, 4720-4744 10.1021/jm500261q
93. For additional SAR see the followingpatent application: Brodney, M. A.; Davoren, J. E.; Garnsey, M. R.; Zhang, L.; O'Neil, S. V. Pyridine derivatives as muscarinic m1 receptor positive allosteric modulators. WO 2016009297, 2016.
94. Kenakin, T. P. A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery, 4 th ed.; Academic Press: San Diego, CA, 2014; pp 469-470.
95. Dasari, S.; Gulledge, A. T. M1 and M4 receptors modulate hippocampal pyramidal neurons J. Neurophysiol. 2011, 105, 779-792 10.1152/jn.00686.2010
96. Langmead, C. J.; Austin, N. E.; Branch, C. L.; Brown, J. T.; Buchanan, K. A.; Davies, C. H.; Forbes, I. T.; Fry, V. A.; Hagan, J. J.; Herdon, H. J.; Jones, G. A.; Jeggo, R.; Kew, J. N.; Mazzali, A.; Melarange, R.; Patel, N.; Pardoe, J.; Randall, A. D.; Roberts, C.; Roopun, A.; Starr, K. R.; Teriakidis, A.; Wood, M. D.; Whittington, M.; Wu, Z.; Watson, J. Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1 Br. J. Pharmacol. 2008, 154, 1104-1115 10.1038/bjp.2008.152
97. Ehlert, F. J. Analysis of allosterism in functional assays. J J. Pharmacol. Exp. Ther. 2005, 315, 740-754 10.1124/jpet.105.090886
98. Kenakin, T. New concepts in drug discovery: collateral efficacy and permissive antagonism Nat. Rev. Drug Discovery 2005, 4, 919-927 10.1038/nrd1875
99. Price, M. R.; Baillie, G. L.; Thomas, A.; Stevenson, L. A.; Easson, M.; Goodwin, R.; McLean, A.; McIntosh, L.; Goodwin, G.; Walker, G.; Westwood, P.; Marrs, J.; Thomson, F.; Cowley, P.; Christopoulos, A.; Pertwee, R. G.; Ross, R. A. Allosteric modulation of the cannabinoid CB1 receptor Mol. Pharmacol. 2005, 68, 1484-1495 10.1124/mol.105.016162
100. Kenakin, T. Gaddum Memorial Lecture 2014: receptors as an evolving concept: from switches to biased microprocessors Br. J. Pharmacol. 2015, 172, 4238-4253 10.1111/bph.13217
101. Ehlert, F. J.; Thomas, E. A. Functional role of M2 muscarinic receptors in the guinea pig ileum Life Sci. 1995, 56, 965-971 10.1016/0024-3205(94)00035-Q
102. Ehlert, F. J.; Griffin, M. T.; Sawyer, G. W.; Bailon, R. A simple method for estimation of agonist activity at receptor subtypes: comparison of native and cloned M3 muscarinic receptors in guinea pig ileum and transfected cells J. Pharmacol. Exp. Ther. 1999, 289, 981-992
103. Vanover, K. E.; Veinbergs, I.; Davis, R. E. Antipsychotic-like behavioral effects and cognitive enhancement by a potent and selective muscarinic M-sub-1 receptor agonist, AC-260584 Behav. Neurosci. 2008, 122, 570-575 10.1037/0735-7044.122.3.570
104. Jones, C. K.; Brady, A. E.; Davis, A. A.; Xiang, Z.; Bubser, M.; Tantawy, M. N.; Kane, A. S.; Bridges, T. M.; Kennedy, J. P.; Bradley, S. R.; Peterson, T. E.; Ansari, M. S.; Baldwin, R. M.; Kessler, R. M.; Deutch, A. Y.; Lah, J. J.; Levey, A. I.; Lindsley, C. W.; Conn, P. J. Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats J. Neurosci. 2008, 28, 10422-10433 10.1523/JNEUROSCI.1850-08.2008
105. Popiolek, M.; Nguyen, D.; Reinhart, V.; Edgerton, J.; Harms, J.; Lotarski, S. M.; Steyn, S. J.; Davoren, J. E.; Grimwood, S., Quantifying CNS M1 muscarinic aetylcholine receptor modulation using an in-vivo IP1 accumulation assay. Unpublished results.
106. Tracy, J. I.; Monaco, C.; Giovannetti, T.; Abraham, G.; Josiassen, R. C. Anticholinergicity and cognitive processing in chronic schizophrenia Biol. Psychol. 2001, 56, 1-22 10.1016/S0301-0511(00)00083-1
107. Vinogradov, S.; Fisher, M.; Warm, H.; Holland, C.; Kirshner, M. A.; Pollock, B. G. The cognitive cost of anticholinergic burden: decreased response to cognitive training in schizophrenia Am. J. Psychiatry 2009, 166, 1055-1062 10.1176/appi.ajp.2009.09010017
108. Minzenberg, M. J.; Poole, J. H.; Benton, C.; Vinogradov, S. Association of anticholinergic load with impairment of complex attention and memory in schizophrenia Am. J. Psychiatry 2004, 161, 116-124 10.1176/appi.ajp.161.1.116
109. Kumari, V.; Soni, W.; Mathew, V. M.; Sharma, T. Prepulse inhibition of the startle response in men with schizophrenia: effects of age of onset of illness, symptoms, and medication Arch. Gen. Psychiatry 2000, 57, 609-614 10.1001/archpsyc.57.6.609
110. Alt, A.; Pendri, A.; Bertekap, R. L., Jr.; Li, G.; Benitex, Y.; Nophsker, M.; Rockwell, K. L.; Burford, N. T.; Sum, C. S.; Chen, J.; Herbst, J. J.; Ferrante, M.; Hendricson, A.; Cvijic, M. E.; Westphal, R. S.; O'Connell, J.; Banks, M.; Zhang, L.; Gentles, R. G.; Jenkins, S.; Loy, J.; Macor, J. E. Evidence for classical cholinergic toxicity associated with selective activation of M1 muscarinic receptors J. Pharmacol. Exp. Ther. 2016, 356, 293-304 10.1124/jpet.115.226910
111. Cruickshank, J. W.; Brudzynski, S. M.; McLachlan, R. S. Involvement of M1 muscarinic receptors in the initiation of cholinergically induced epileptic seizures in the rat brain Brain Res. 1994, 643, 125-129 10.1016/0006-8993(94)90017-5
112. Hamilton, S. E.; Loose, M. D.; Qi, M.; Levey, A. I.; Hille, B.; McKnight, G. S.; Idzerda, R. L.; Nathanson, N. M. Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 13311-13316 10.1073/pnas.94.24.13311
113. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292340.pdf (accessed February 11, 2016).
114. Friesen, D. T.; Shanker, R.; Crew, M.; Smithey, D. T.; Curatolo, W. J.; Nightingale, J. A. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview Mol. Pharmaceutics 2008, 5, 1003-1019 10.1021/mp8000793