ABSTRACT
Herein we describe the discovery and optimization of a new series of 2,3-disubstituted and 2,3,6-trisubstituted muscarinic acetylcholine receptorâ 4 (M4 ) positive allosteric modulators (PAMs). Iterative libraries enabled rapid exploration of one-dimensional structure-activity relationships (SAR) and identification of potency-enhancing heterocycle and N-alkyl pyrazole substituents. Further optimization led to identification of the potent, receptor-subtype-selective, brain-penetrant tool compound 24 (7-[3-[1-[(1-fluorocyclopentyl)methyl]pyrazol-4-yl]-6-methyl-2-pyridyl]-3-methoxycinnoline). It is efficacious in preclinical assays that are predictive of antipsychotic effects, producing dose-dependent reversal of amphetamine-induced hyperlocomotion in rats and mice, but not in M4 knockout mice. Cholinergic-related adverse effects observed in rats treated with 24 at unbound plasma concentrations more than 3-fold higher than an efficacious dose in the hyperlocomotion assay were fewer and less severe than those observed in rats treated with the nonselective M4 agonist xanomeline, suggesting a receptor-subtype-selective PAM has the potential for an improved safety profile.
Subject(s)
Drug Discovery , Pyridines/chemistry , Pyridines/pharmacology , Receptor, Muscarinic M4/drug effects , Allosteric Regulation , Animals , Humans , Rats , Receptor, Muscarinic M4/metabolism , Structure-Activity RelationshipABSTRACT
We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Kiâ¯=â¯22.4⯵M), exhibited good binding efficiencies (LBEâ¯=â¯0.49, LLEâ¯=â¯4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Drug Design , Phosphodiesterase Inhibitors/chemistry , Animals , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Half-Life , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Conformation , Molecular Dynamics Simulation , Phosphodiesterase Inhibitors/metabolism , Phosphodiesterase Inhibitors/pharmacokinetics , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Pyrimidines/chemistry , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.
Subject(s)
Isoindoles/chemical synthesis , Neurokinin-1 Receptor Antagonists/chemical synthesis , Oxazoles/chemical synthesis , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Drug Interactions , Glucuronides/metabolism , Humans , Isoindoles/chemistry , Isoindoles/pharmacokinetics , Isoindoles/pharmacology , Metabolic Clearance Rate , Neurokinin-1 Receptor Antagonists/chemistry , Neurokinin-1 Receptor Antagonists/pharmacokinetics , Neurokinin-1 Receptor Antagonists/pharmacology , Oxazoles/chemistry , Oxazoles/pharmacokinetics , Oxazoles/pharmacology , Peptide Fragments/pharmacology , Substance P/analogs & derivatives , Substance P/pharmacologyABSTRACT
An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M(1) positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.
Subject(s)
Carboxylic Acids/chemical synthesis , Quinolines/chemistry , Receptor, Muscarinic M1/metabolism , Allosteric Regulation , Animals , Blood Proteins/chemistry , Blood Proteins/metabolism , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Humans , Protein Binding , Rats , Small Molecule LibrariesABSTRACT
3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.
