Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M ₁ Positive Allosteric Modulators

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.