Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M1 positive allosteric modulators

A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M₁ positive allosteric modulators. A methoxy group was optimal for M₁ activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.     

Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor

Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer’s disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM’s) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor. Low-shift PAM’s offer the potential of “use-dependent” attenuation of transmitter-signaling while avoiding pseudo-agonistic behavior in vivo as a common limitation of the so far described high-shift PAM’s. With these novel M1-PAM’s, the M1 receptor is potentially the first GPCR for which both, high- and low shift PAM’s have become available.     

Quinolizidinone carboxylic acid selective M1 allosteric modulators: SAR in the piperidine series

SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M₁ positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.     

Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe

This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M₁ PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M₁ PAM with an in vitro profile comparable to the prototypical M₁ PAM, BQCA, but with an improved brain to plasma ratio.     

Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1

Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu₁ using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds.     

Efficacy switching SAR of mGluR5 allosteric modulators: highly potent positive and negative modulators from one chemotype

A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed.     

N-Heterocyclic derived M1 positive allosteric modulators

Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M₁ positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.     

Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor

The M₃ muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure­-activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M₃ mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M₃ mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M₁, M₂, and M₄ mAChRs, and moderate selectivity over the M₅ mAChR, indicating that compound 9 is an M₃-preferring M₃/M₅ dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M₃ mAChR for further investigation of its pharmacological function both in vitro and in vivo.     

Benzobistriazinones and related heterocyclic ring systems as potent, orally bioavailable positive allosteric AMPA receptor modulators

AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted benzobistriazinone, benzobispyrimidinone and related derivatives have been prepared with high potency and selectivity for the allosteric binding site of AMPARs. Further improvements have been made to previously reported series of positive AMPAR modulators and these compounds exhibit excellent in vivo activity and improved in vivo metabolic stability with up to 100% oral bioavailability in rat.     

Heterocyclic fused pyridone carboxylic acid M1 positive allosteric modulators

The phenyl ring in a series of quinolone carboxylic acid M₁ positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure.     

Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes

This Letter details our efforts to develop new M₄ PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4-h]quinazoline core and an 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M₄.     

Hydroxy cycloalkyl fused pyridone carboxylic acid M1 positive allosteric modulators

Incorporation of hydroxycycloalkyl fused pyridone carboxylic acids in lieu of quinolone carboxylic acids enhance free fraction without increased susceptibility to P-glycoprotein transport.     

Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators

A new series of potent fused thiazole mGlu₅ receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu₅ PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu₅ negative allosteric modulators (NAMs).     

Optimization of M4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology

This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M₄ positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson’s disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.     

Pyridine containing M1 positive allosteric modulators with reduced plasma protein binding

Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M₁ positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure.     

Discovery of a novel 3,4-dimethylcinnoline carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping

This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M₄ PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M₄ PAM activity and improved clearance and protein binding profiles.     

Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping

This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M₄ PAM activity in most M₄ PAMs to date, within the thieno[2,3-b]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M₄ PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core.     

Structure based evolution of a novel series of positive modulators of the AMPA receptor

Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.     

Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators

The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis’ AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development.     

Heterobiaryl and heterobiaryl ether derived M5 positive allosteric modulators

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M₅-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G_q mAChR M₁, M₃, M₅ PAM. An iterative parallel synthesis approach was employed to incorporate basic heterocycles to improve physiochemical properties.