Aminopiperidine indazoles as orally efficacious melanin concentrating hormone receptor-1 antagonists

The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.     

Design and synthesis of orally efficacious benzimidazoles as melanin-concentrating hormone receptor 1 antagonists

Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.     

Cyclic benzamidines as orally efficacious NR2B-selective NMDA receptor antagonists

A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain.     

Design,synthesis, and biological evaluation of novel diarylalkyl amides as TRPV1 antagonists

We have developed a new class of diarylalkyl amides as novel TRPV1 antagonists. They exhibited potent ⁴⁵Ca²⁺ uptake inhibitions in rat DRG neuron. In particular, the amide 59 was identified as a potent antagonist with IC₅₀ of 57 nM. The synthesis and structure–activity relationship of the diarylalkyl amides are also described.     

Tetrahydro-naphthols as orally available TRPV1 inhibitors

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead's phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level.     

Potent, orally absorbed glucagon receptor antagonists

The SAR of 2-pyridyl-3,5-diaryl pyrroles, ligands of the human glucagon receptor and inhibitors of p38 kinase, were investigated. This effort resulted in the identification of 2-(4-pyridyl)-5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)pyrr ole 49 (L-168,049), a potent (Kb = 25 nM), selective antagonist of glucagon.     

Identification of potent, soluble, and orally active TRPV1 antagonists

Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.     

Spiro-piperidine azetidinones as potent TRPV1 antagonists

A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists. An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to the discovery of a potent antagonist with good oral pharmacokinetic profile in rat.     

Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.     

Synthesis of benzamide derivatives as TRPV1 antagonists

From hit compounds identified by high throughput screening (HTS), we have found compound 1 as a lead TRPV1 antagonist and confirmed its potential as a treatment for pain. Compound 1 has led to potent TRPV1 antagonistic benzamide derivatives ((+/-)-2: human IC(50)=23 nM, (+/-)-3: human IC(50)=14 nM in the capsaicin-induced calcium influx assay) containing indole and naphthyl moieties, obtained by elaboration of the tryptamine scaffold or via bioisosteric replacements.     

Discovery of benzothiazole derivatives as efficacious and enterocyte-specific MTP inhibitors

A series of triamide derivatives bearing a benzothiazole core is shown to be potent microsomal triglyceride transfer protein (MTP) inhibitors. In order to minimize liver toxicity, these compounds have been optimized to have activity only in the enterocytes and have limited systemic bioavailability. Upon oral administration, selected analogs within this series have been further demonstrated to reduce food intake along with body weight and thereby improve glucose homeostasis and insulin sensitivity in a 28-day mice diet-induced obesity (DIO) model.     

Synthesis and structural optimization of multiple H-bonding region of diarylalkyl (thio)amides as novel TRPV1 antagonists

Structural optimization of multiple H-bonding region and structure–activity relationship of diarylalkyl amides/thioamides as novel TRPV1 antagonists are described. In particular, we identified amide 34o and thioamides 35o and 35r, of which antagonistic activities were highly enhanced by an incorporation of cyano or vinyl-substituent to the multiple H-bonding region. They exhibited potent ⁴⁵Ca²⁺ uptake inhibitions in rat DRG neuron with IC₅₀s of 25, 32 and 28 nM, respectively.     

Design,synthesis, and biological evaluation of novel biphenyl-4-carboxamide derivatives as orally available TRPV1 antagonists

A new series of transient receptor potential vanilloid type 1 (TRPV1) antagonists were designed and synthesized from N-(3-hydroxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride (8). SAR studies identified (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide hydrochloride (ASP8370, 7), as a compound with high aqueous solubility, satisfactory stability in human liver microsomes, and reduced CYP3A4 inhibition. ASP8370 was selected as a clinical development candidate with significant ameliorative effects on neuropathic pain. SAR studies also revealed the structural mechanisms underlying the switching between TRPV1 antagonism and agonism.     

Discovery of benzothiazole amides as potent antimycobacterial agents

From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12?μg/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1–2?μg/mL against Mycobacterium avium complex. The preliminary mechanism of action studies suggested these agents may target MmpL3, a mycobacterial mycolic acid transporter. The series has demonstrated in vivo efficacy in a proof of concept mouse model of M. abscessus infection.     

Substituted aryl pyrimidines as potent and soluble TRPV1 antagonists

Clinical candidate AMG 517 (1) is a potent antagonist toward multiple modes of activation of TRPV1; however, it suffers from poor solubility. Analogs with various substituents at the R region of 3 were prepared to improve the solubility while maintaining the potent TRPV1 activity of 1. Compounds were identified that maintained potency, had good pharmacokinetic properties, and improved solubility relative to 1.     

Piperidyl amides as novel,potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity

High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation.     

Discovery of indane propanamides as potent and selective TRPV1 antagonists

A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure–activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase.     

Heteroaryl beta-tetralin ureas as novel antagonists of human TRPV1

We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.     

Discovery and optimization of pyrazole amides as antagonists of CCR1

A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.     

Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.