Herein, we report
the discovery of the first selective and CNS
penetrant mGlu7 PAM (VU6027459) derived from a “molecular
switch” within a selective mGlu7 NAM chemotype.
VU6027459 displayed CNS penetration in both mice (Kp =
2.74) and rats (Kp= 4.78), it was orally bioavailable in
rats (%F = 69.5), and undesired activity at DAT was ablated.
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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