ABSTRACT
We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5â¯mg/kg/h.
Subject(s)
Benzamides/pharmacology , Brain/drug effects , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridazines/pharmacology , Benzamides/chemical synthesis , Benzamides/chemistry , Brain/metabolism , Dose-Response Relationship, Drug , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridazines/chemical synthesis , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.
Subject(s)
Benzamides/pharmacology , Drug Discovery , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Benzamides/administration & dosage , Benzamides/chemistry , Dose-Response Relationship, Drug , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.