TY - JOUR
T1 - Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M 1 Positive Allosteric Modulators
AU - Engers, Julie L.
AU - Bender, Aaron M.
AU - Kalbfleisch, Jacob J.
AU - Cho, Hyekyung P.
AU - Lingenfelter, Kaelyn S.
AU - Luscombe, Vincent B.
AU - Han, Changho
AU - Melancon, Bruce J.
AU - Blobaum, Anna L.
AU - Dickerson, Jonathan W.
AU - Rook, Jerri M.
AU - Niswender, Colleen M.
AU - Emmitte, Kyle A.
AU - Conn, P. Jeffrey
AU - Lindsley, Craig W.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/3/20
Y1 - 2019/3/20
N2 - This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M 1 ) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M 1 agonism, e.g., no M 1 ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL p < 8 mL/min/kg and t 1/2 > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant (K p < 0.05), despite a lack of hydrogen bond donors. However, removal of a single nitrogen atom to afford imidazopyridine derivatives proved to retain the excellent rat PK and provide high CNS penetration (K p > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M 1 agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M 1 PAMs across the diverse tricyclic heterocyclic cores possessed equivalent CNS MPO scores (>4.5), highlighting the value of both "medicinal chemist's eye" and experimental data, e.g., not sole reliance (or decision bias) on in silico calculated properties, for parameters as complex as CNS penetration.
AB - This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M 1 ) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M 1 agonism, e.g., no M 1 ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL p < 8 mL/min/kg and t 1/2 > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant (K p < 0.05), despite a lack of hydrogen bond donors. However, removal of a single nitrogen atom to afford imidazopyridine derivatives proved to retain the excellent rat PK and provide high CNS penetration (K p > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M 1 agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M 1 PAMs across the diverse tricyclic heterocyclic cores possessed equivalent CNS MPO scores (>4.5), highlighting the value of both "medicinal chemist's eye" and experimental data, e.g., not sole reliance (or decision bias) on in silico calculated properties, for parameters as complex as CNS penetration.
KW - CNS
KW - M
KW - PAM
KW - Positive allosteric modulator
KW - SAR
KW - muscarinic acetylcholine receptor 1
UR - http://www.scopus.com/inward/record.url?scp=85052393816&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.8b00311
DO - 10.1021/acschemneuro.8b00311
M3 - Article
C2 - 30086237
AN - SCOPUS:85052393816
SN - 1948-7193
VL - 10
SP - 1035
EP - 1042
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 3
ER -