1201924-34-6Relevant articles and documents
Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M1 Positive Allosteric Modulators
Engers, Julie L.,Bender, Aaron M.,Kalbfleisch, Jacob J.,Cho, Hyekyung P.,Lingenfelter, Kaelyn S.,Luscombe, Vincent B.,Han, Changho,Melancon, Bruce J.,Blobaum, Anna L.,Dickerson, Jonathan W.,Rook, Jerri M.,Niswender, Colleen M.,Emmitte, Kyle A.,Conn, P. Jeffrey,Lindsley, Craig W.
, p. 1035 - 1042 (2019)
This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M1) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M1 agonism, e.g., no M1 ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CLp 1/2 > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant (Kp p > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M1 agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M1 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.
PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
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Page/Page column 62-63, (2018/05/24)
Compounds of Formula I and methods of use as Interleukin-1 Receptor Associated Kinase 4 (IRAK4) inhibitors are described herein.
INDOLIN-2-ONE DERIVATIVES
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Page/Page column 47, (2017/06/15)
The present invention is concerned with indolin-2-one derivatives of general formula (I) wherein the substituents are defined in claim 1. The compounds may be used in the treatment of CNS diseases related to positive (psychosis) and negative symptoms of s
