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Niswender Laboratory

Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M Positive Allosteric Modulators

AUTHORS

Engers JLJulie L , Bender AMAaron M , Kalbfleisch JJJacob J , Cho HPHyekyung P , Lingenfelter KSKaelyn S , Luscombe VBVincent B , Han CChangho , Melancon BJBruce J , Blobaum ALAnna L , Dickerson JWJonathan W , Rook JMJerri M , Niswender CMColleen M , Emmitte KAKyle A , Conn PJP Jeffrey , Lindsley CWCraig W . ACS chemical neuroscience. 2018 8 9; 10(3). 1035-1042

ABSTRACT

This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M agonism, e.g., no M ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL < 8 mL/min/kg and t > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant ( K < 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 > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M 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.

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