Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides

被引：17

作者：

Tarr, James C. ^{[1
]}

Wood, Michael R. ^{[1
,3
]}

Noetzel, Meredith J. ^{[1
,2
]}

Melancon, Bruce J. ^{[1
]}

Lamsal, Atin ^{[1
,2
]}

Luscombe, Vincent B. ^{[1
]}

Rodriguez, Alice L. ^{[1
]}

Byers, Frank W. ^{[1
]}

Chang, Sichen ^{[1
]}

Cho, Hyekyung P. ^{[1
]}

Engers, Darren W. ^{[1
]}

Jones, Carrie K. ^{[1
,2
]}

Niswender, Colleen M. ^{[1
,2
,5
]}

Wood, Michael W. ^{[4
]}

Brandon, Nicholas J. ^{[4
]}

Duggan, Mark E. ^{[4
]}

Conn, P. Jeffrey ^{[1
,2
,5
]}

Bridges, Thomas M. ^{[1
,2
]}

Lindsley, Craig W. ^{[1
,2
,3
]}

机构：

[1] Vanderbilt Univ, Sch Med, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[4] Astra Zeneca, Neurosci Innovat Med, 141 Portland St, Cambridge, MA 02139 USA

[5] Vanderbilt Univ, Sch Med, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 23期

关键词：

M4; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Azetidine; MUSCARINIC ACETYLCHOLINE-RECEPTOR; POSITIVE ALLOSTERIC MODULATOR; BORONIC ACIDS; SCHIZOPHRENIA; POTENTIATORS; XANOMELINE; COMPOUND; AGONISTS; CORE;

D O I：

10.1016/j.bmcl.2017.10.053

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we describe the continued optimization of M-4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c] pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：5179 / 5184

页数：6

共 30 条

[1] Metal-Free Coupling of Saturated Heterocyclic Sulfonylhydrazones with Boronic Acids [J].

Allwood, Daniel M. ;

Blakemore, David C. ;

Brown, Alan D. ;

Ley, Steven V. .

JOURNAL OF ORGANIC CHEMISTRY, 2014, 79 (01) :328-338

[2]

Barluenga J, 2009, NAT CHEM, V1, P494, DOI [10.1038/NCHEM.328, 10.1038/nchem.328]

[3] Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease [J].

Bodick, NC ;

Offen, WW ;

Levey, AI ;

Cutler, NR ;

Gauthier, SG ;

Satlin, A ;

Shannon, HE ;

Tollefson, GD ;

Rasmussen, K ;

Bymaster, FP ;

Hurley, DJ ;

Potter, WZ ;

Paul, SM .

ARCHIVES OF NEUROLOGY, 1997, 54 (04) :465-473

[4] Centrally Active Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats [J].

Brady, Ashley E. ;

Jones, Carrie K. ;

Bridges, Thomas M. ;

Kennedy, J. Phillip ;

Thompson, Analisa D. ;

Heiman, Justin U. ;

Breininger, Micah L. ;

Gentry, Patrick R. ;

Yin, Huiyong ;

Jadhav, Satyawan B. ;

Shirey, Jana K. ;

Conn, P. Jeffrey ;

Lindsley, Craig W. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 327 (03) :941-953

[5] Selective Activation of M4 Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents [J].

Bubser, Michael ;

Bridges, Thomas M. ;

Dencker, Ditte ;

Gould, Robert W. ;

Grannan, Michael ;

Noetzel, Meredith J. ;

Lamsal, Atin ;

Niswender, Colleen M. ;

Daniels, J. Scott ;

Poslusney, Michael S. ;

Melancon, Bruce J. ;

Tarr, James C. ;

Byers, Frank W. ;

Wess, Juergen ;

Duggan, Mark E. ;

Dunlop, John ;

Wood, Michael W. ;

Brandon, Nicholas J. ;

Wood, Michael R. ;

Lindsley, Craig W. ;

Conn, P. Jeffrey ;

Jones, Carrie K. .

ACS CHEMICAL NEUROSCIENCE, 2014, 5 (10) :920-942

[6] Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100 [J].

Byun, Nellie E. ;

Grannan, Michael ;

Bubser, Michael ;

Barry, Robert L. ;

Thompson, Analisa ;

Rosanelli, John ;

Gowrishankar, Raajaram ;

Kelm, Nathaniel D. ;

Damon, Stephen ;

Bridges, Thomas M. ;

Melancon, Bruce J. ;

Tarr, James C. ;

Brogan, John T. ;

Avison, Malcolm J. ;

Deutch, Ariel Y. ;

Wess, Juergen ;

Wood, Michael R. ;

Lindsley, Craig W. ;

Gore, John C. ;

Conn, P. Jeffrey ;

Jones, Carrie K. .

NEUROPSYCHOPHARMACOLOGY, 2014, 39 (07) :1578-1593

[7] Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia [J].

Chan, W. Y. ;

McKinzie, D. L. ;

Bose, S. ;

Mitchell, S. N. ;

Witkin, J. M. ;

Thompson, R. C. ;

Christopoulos, A. ;

Lazareno, S. ;

Birdsall, N. J. M. ;

Bymaster, F. P. ;

Felder, C. C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (31) :10978-10983

[8] Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M2 and M4 Receptors [J].

Croy, Carrie H. ;

Schober, Douglas A. ;

Xiao, Hongling ;

Quets, Anne ;

Christopoulos, Arthur ;

Felder, Christian C. .

MOLECULAR PHARMACOLOGY, 2014, 86 (01) :106-115

[9] Allosteric Antipsychotics: M4 Muscarinic Potentiators as Novel Treatments for Schizophrenia [J].

Farrell, Martilias ;

Roth, Bryan L. .

NEUROPSYCHOPHARMACOLOGY, 2010, 35 (04) :851-852

[10] Recent Developments in Negishi Cross-Coupling Reactions [J].

Haas, Diana ;

Hammann, Jeffrey M. ;

Greiner, Robert ;

Knochel, Paul .

ACS CATALYSIS, 2016, 6 (03) :1540-1552

← 1 2 3 →