Abstract
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.