Discovery of δ opioid receptor full agonists lacking a basic nitrogen atom and their antidepressant-like effects

We have recently reported that the elaboration of the N-substituent in the δ opioid receptor (DOR) antagonist naltrindole (NTI) enabled the regulation of the DOR activities from full inverse agonists to weak partial agonists. The investigations of amide-type NTI derivatives revealed that N-phenylacetyl and N-dihydrocinnamoyl derivatives 3a and 3b were DOR full agonists. The same transformations were applied to a DOR agonist KNT-127 to provide the more potent DOR agonists 6a and 6b. Among the tested compounds, the most efficacious compound 6a showed dose-dependent antidepressant-like effects in the mouse forced swim test. The antidepressant-like effects by 6a seemed to be more potent than those of KNT-127, which is a more potent DOR agonist in in vitro assays. The amide-type compound like 6a may more fully penetrate into the central nervous system.     

Novel multifunctional dopamine D2/D3 receptors agonists with potential neuroprotection and anti-alpha synuclein protein aggregation properties

Our ongoing drug development endeavor to design compounds for symptomatic and neuroprotective treatment of Parkinson’s disease (PD) led us to carry out a structure activity relationship study based on dopamine agonists pramipexole and 5-OHDPAT. Our goal was to incorporate structural elements in these agonists in a way to preserve their agonist activity while producing inhibitory activity against aggregation of α-synuclein protein. In our design we appended various catechol and related phenol derivatives to the parent agonists via different linker lengths. Structural optimization led to development of several potent agonists among which (−)-8a, (−)-14 and (−)-20 exhibited potent neuroprotective properties in a cellular PD model involving neurotoxin 6-OHDA. The lead compounds (−)-8a and (−)-14 were able to modulate aggregation of α-synuclein protein efficiently. Finally, in an in vivo PD animal model, compound (−)-8a exhibited efficacious anti-parkinsonian effect.     

Identification and immunological evaluation of novel TLR2 agonists through structure optimization of Pam3CSK4

Toll-like receptor 2 (TLR2) is a bridge between innate immunity and adaptive immunity. TLR2 agonists have been exploited as potential vaccine adjuvants and antitumor agents. However, no TLR2 agonists have been approved by FDA up to now. To discover drug-like TLR2 selective agonists, a novel series of Pam₃CSK₄ derivatives were designed based on the crystal structure of hTLR2-hTLR1-Pam₃CSK₄ complex, synthesized and evaluated for their immune-stimulatory activities. Among them, 35c was identified as a murine-specific TLR2 agonist, while 35f was a human-specific TLR2 agonist. Besides, 35d (human and murine TLR2 agonist) showed TLR2 agonistic activity comparable to Pam₃CSK₄, which included: elevated IL-6 expression level (EC₅₀ = 83.08 ± 5.94 nM), up-regulated TNF-α and IL-6 mRNA expression and promoted maturation of DCs through activating the NF-κB signaling pathway. TLRs antibodies test showed that 35a and 35d were TLR2/1 agonists, while 35f was a TLR2/6 agonist.     

Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration

We designed and synthesized novel δ opioid receptor (DOR) agonists 3a–i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton. As a result, 3b showed potent antinociceptive effects.     

Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis

A series of libraries were designed using the 1-(cyclopropylmethyl)-2-alkyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium templates 2a–b, and Sulfonamide derivatives 11a–n proved to be potent agonists of the CB₂ receptor. Analysis of the Lipophilic Efficiency (LipE) of potent compounds provided new insight for the design of potent, metabolically stable CB2 agonists.     

Synthesis and evaluation of novel fused pyrimidine derivatives as GPR119 agonists

A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16, 19, 26, 28, 42) bearing endo-N-Boc-nortropane amine and fluoro-substituted aniline exhibited better EC₅₀ values (0.27–1.2 μM) though they appeared to be partial agonists.     

Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.     

2-Amino-9-aryl-3-cyano-4-methyl-7-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]thieno[2,3-b]pyridine derivatives as selective progesterone receptor agonists

High throughput screening of the corporate compound collection led to the identification of a novel series of 2-amino-9-aryl-3-cyano-4-methyl-7-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]thieno[2,3-b]pyridine derivatives as selective PR agonists. Initial SAR exploration leading to potent and selective agonists 9 and 11, X-ray crystal structure of 9 bound to PR-LBD and preliminary developability data are described.     

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2–4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2–4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.     

Synthesis,biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novel β2-adrenoceptor agonists

A novel series of 2-amino-2-phenylethanol derivatives were developed as β₂-adrenoceptor agonists. Among them, 2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile (compound 2f) exhibited the highest activity (EC₅₀ = 0.25 nM) in stimulating β₂-adrenoceptor-mediated cellular cAMP production with a 763.6-fold selectivity over the β₁-adrenoceptor. The (S)-isomer of 2f was subsequently found to be 8.5-fold more active than the (R)-isomer. Molecular docking was performed to determine the putative binding modes of this new class of β₂-adrenoceptor agonists. Taken together, these data show that compound 2f is a promising lead compound worthy of further study for the development of β₂-adrenoceptor agonists.     

Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT6 agonists

A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a–z was prepared as novel 5-HT₆ ligands. The best compounds were high affinity, full agonists at 5-HT₆ receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.     

Discovery and SAR of para-alkylthiophenoxyacetic acids as potent and selective PPARδ agonists

Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARδ agonists.     

2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists

N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC₅₀ values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC₅₀ = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC₅₀ = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.     

Discovery of novel orally bioavailable GPR40 agonists

The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. A series of novel orally bioavailable GPR40 agonists was discovered. SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys.     

Discovery,structure–activity relationship studies,and anti-nociceptive effects of 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one as novel opioid receptor agonists

The μ-opioid receptor (MOR) is the major opioid receptor targeted by most analgesics in clinical use. However, the use of all known MOR agonists is associated with severe adverse effects. We reported that the 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-ones are novel opioid receptor agonists. Subsequent structural modification resulted in the potent MOR/KOR (κ-opioid receptor) agonists 19, 20, and 21. Testing the analgesic effect of these in WT B6 mice (tail-flick test) gave ED₅₀ values of 8.4, 10.9, and 26.6 mg/kg, respectively. The 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one core could be addressed in 1 or 2 synthetic steps with moderate to high percent of yield. In the adenylyl cyclase assay, compound 19 displayed a MOR/KOR agonist profile, with IC₅₀ values of 0.73 and 0.41 μM, respectively. Current results suggest that compound 19 is a promising lead to go further development and in vitro/in vivo adverse effects studies.     

Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation

Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure–activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1–10 μM. The order of agonistic activity toward both PPARγ/RXRα and LXRα/RXRα was the same as it was for RXR, that is, 11 > 10 > 12. These results should be useful for the development of RXR agonists with improved bioavailability.     

Synthesis and pharmacological evaluation of new arylpiperazines. 3-{4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-quinazolidin-4-one — a dual serotonin 5-HT1A/5-HT2A receptor ligand with an anxiolytic-like activity

On the basis of systematic studies on the structure–activity relationships in arylpiperazine group of serotonin ligands, 12 new derivatives containing quinazolidin-4(3H)-one (1–4), 2-phenyl-2,3-dihydrophthalazine-1,4-dione (5–8) or 1-phenyl-1,2-dihydropyridazine-3,6-dione (9–12) fragments were synthesized. The majority of the tested compounds (2, 4, 7, 8 and 10–12) showed a high affinity for 5-HT_1A receptors (K_i=11–54 nM) and two (1, 2) were found active at 5-HT_2A sites (16 and 68 nM, respectively). All the new 5-HT_1A ligands tested in vivo revealed an antagonistic activity at postsynaptic 5-HT_1A receptors, and three of them behaved as agonists at presynaptic ones. Additionally, both the meta-chlorophenylpiperazine derivatives containing quinazolidin-4-one fragment showed features of 5-HT_2A receptor antagonists. The dual 5-HT_1A/5-HT_2A receptor ligand (2) was further tested for its potential psychotropic activity. It showed a distinct anxiolytic-like activity in a conflict drinking test in rats and the observed effect was more potent in terms of the active dose, than that produced by diazepam (used as a reference drug).     

Switching cannabinoid response from CB2 agonists to FAAH inhibitors

A series of 3-carboxamido-5-aryl-isoxazoles designed as CB₂ agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure–activity relationships enabling to switch cannabinoid response from CB₂ agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB₂ activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.     

Design,synthesis, and biological evaluation of novel dual FFA1 (GPR40)/PPARδ agonists as potential anti-diabetic agents

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) were considered as potential anti-diabetic targets, and the dual FFA1/PPARδ agonists might provide synergistic effect in insulin secretion and sensibility. Herein, we further develop dual agonists by screening 7 series of heterocycles, resulting in the discovery of compound 19 with considerable oral pharmacokinetic profile. Compound 19 exhibited a balanced potency between FFA1 and PPARδ, and high selectivity over PPARα and PPARγ. Moreover, compound 19 exerted improved glucose-lowering effects and insulin sensitivity in a dose-dependent manner, which might be attributed to its dual effects to simultaneously regulate insulin secretion and resistance. Our results extended the existing chemical space, and provided a potent tool compound 19.