Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box.

Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity.

Synthesis and evaluation of carbamate and aryl ether substituted pyrazinones as corticotropin releasing factor-1 (CRF₁) receptor antagonists.

A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.

Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5.

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile.

Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors.

Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models.

Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist.

A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported.

Conformationally restricted homotryptamines. Part 6: indole-5-cycloalkyl methylamines as selective serotonin reuptake inhibitors.

Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds.

Potential CRF1R PET imaging agents: 1-fluoroalkylsubstituted 5-halo-3-(arylamino)pyrazin-2(1H)-ones.

A series of pyrazinones were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients are discussed herein.

[18F](R)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(4-(2-fluoroethoxy)-2,5-dimethyl phenylamino)pyrazin-2(1H)-one: introduction of N3-phenylpyrazinones as potential CRF-R1 PET imaging agents.

Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [(18)F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments.

Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists.

A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized.

Potential CRF1R PET imaging agents: N-fluoroalkyl-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines.

A series of N-fluoroalkyl-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients resulted in discovery of analog 7e (IC(50)=6.5 nM, logD=3.

Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors.

A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3-positions, respectively. Nitrile and fluoro substitutions at the indole 5-position gave highest hSERT potency.

Synthesis and structure-activity relationships of N3-pyridylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists.

A series of N(3)-pyridylpyrazinones was investigated as corticotropin-releasing factor-1 receptor antagonists. It was observed that the binding affinity of analogues containing a pyridyl group was influenced not only by the substitution pattern on the pyridyl group, but also by the pK(a) of the pyridyl nitrogen. Analogues containing a novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group were among the most potent N(3)-pyridylpyrazinones synthesized.

Synthesis and hSERT activity of homotryptamine analogs. Part 6: [3+2] dipolar cycloaddition of 3-vinylindoles.

Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT).

Conformationally restricted homotryptamines. Part 5: 3-(trans-2-aminomethylcyclopentyl)indoles as potent selective serotonin reuptake inhibitors.

A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT.

Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists.

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.

Pharmacological characterization and appetite suppressive properties of BMS-193885, a novel and selective neuropeptide Y(1) receptor antagonist.

Treatment of obesity is still a large unmet medical need. Neuropeptide Y is the most potent orexigenic peptide in the animal kingdom. Its five cloned G-protein couple receptors are all implicated in the regulation of energy homeostasis evidenced by overexpression or deletion of neuropeptide Y or its receptors.

Ex vivo assessment of binding site occupancy of monoamine reuptake inhibitors: methodology and biological significance.

The goal of this study was to develop and validate ex vivo binding assays for serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, and to use these assays to evaluate the binding site occupancy of triple and double monoamine reuptake inhibitors in rat brains. This study demonstrated that while autoradiographic methods provided anatomic precision and regional resolution, the homogenate binding method for site occupancy assessment yielded comparable sensitivity with markedly improved throughput. For ex vivo binding assays, the reduction of temperature and time during the in vitro process (primarily incubation with a radioligand) markedly decreased the dissociation of test agents from binding sites in brain tissues.

Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor.

A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.

Conformationally restricted homotryptamines 3. Indole tetrahydropyridines and cyclohexenylamines as selective serotonin reuptake inhibitors.

A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a.

Synthesis and evaluation of 5,5-diphenylimidazolones as potent human neuropeptide Y5 receptor antagonists.

A series of novel 5,5-diphenylimidazolones was synthesized and evaluated for activity against the human neuropeptide Y5 receptor. The 3-pyridyl analog 46 demonstrated an IC(50) of 8.3 nM with a favorable pharmacokinetic profile in rats, but was ineffective in reducing food intake.

Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors.

A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis.

Homotryptamines as potent and selective serotonin reuptake inhibitors (SSRIs).

A series of N,N-dimethylhomotryptamines was prepared and their binding affinities at the serotonin transporter (SERT) were determined. Compounds possessing an electron withdrawing substituent at the C5-position of the indole nucleus were found to be potent SSRIs. Initial attempts at conformational restriction of the propylamine sidechain by incorporation of a quinuclidine bicyclic structure did not improve binding affinity at SERT.

Isosteric N-arylpiperazine replacements in a series of dihydropyridine NPY1 receptor antagonists.

4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY1 receptor antagonists. These were prepared by a ZnCl2-mediated reductive amination reaction between elaborated primary amines, 2 or 5, and 4-arylpiperidones.

beta-alanine dipeptides as MC4R agonists.

beta-Alanine derivative 2 (IC(50)=16 nM) and related compounds were found to be potent MC4R agonists.