Estrogen receptor beta ligands: design and synthesis of new 2-phenyl-isoindole-1,3-diones

The design, synthesis, and biological evaluation of the 2-phenyl-isoindole-1,3-diones will be discussed. Detailed modeling studies with X-ray support were used to understand the ligand binding orientation and observed selectivity.     

Enantioselective synthesis of 1-methoxy- and 1-deoxy-2'-methyl-delta8-tetrahydrocannabinols: new selective ligands for the CB2 receptor

Two new series of cannabinoids were prepared and their affinities for the CB1 and CB2 receptors were determined. These series are the (2'R)- and (2'S)-1-methoxy- and 1-deoxy-3-(2'-methylalkyl)-delta8-tetrahydrocannabinols, with alkyl side chains of three to seven carbon atoms. These compounds were prepared by a route that employed the enantioselective synthesis of the resorcinol precursors to the cannabinoid ring system. All of these compounds have greater affinity for the CB2 receptor than the CB1 receptor and four of them, (2'R)-1-methoxy-3-(2'-methylbutyl)-delta8-THC (JWH-359), (2'S)-1-deoxy-3-(2'-methylbutyl)-delta8-THC (JWH-352), (2'S)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), and (2'R)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), have good affinity (K(i) = 13-47 nM) for the CB2 receptor and little affinity (K(i) = 1493 to >10,000 nM) for the CB1 receptor. In the 1-deoxy-3-(2'-methylalkyl)-delta8-THC series, the 2'S-methyl compounds in general have greater affinity for the CB2 receptor than the corresponding 2'R isomers.     

Synthesis and activity of a new class of pathway-selective estrogen receptor ligands: hydroxybenzoyl-3,4-dihydroquinoxalin-2(1H)-ones

The anti-inflammatory activity of non-selective estrogens has been attributed to their ability to antagonize the activity of nuclear factor kappaB (NF-kappaB), a known mediator of inflammatory responses. Here we report the identification of a potent new class of pathway-selective ER ligands that selectively antagonize NF-kappaB functional activity, while exhibiting a lack of classical estrogenic effect.     

Preparation of 3-spirocyclic indolin-2-ones as ligands for the ORL-1 receptor

A novel series of indolin-2-ones having a spirocyclic piperidine ring at the 3-position was synthesized and found to bind with high affinity to the ORL-1 receptor. Structure-activity relationships at the piperidine nitrogen were investigated. Substitution on the phenyl ring and nitrogen atom of the indolin-2-one core generated several selective high-affinity ligands that were antagonists of the ORL-1 receptor.     

Estrogen receptor ligands. Part 10: Chromanes: old scaffolds for new SERAMs

The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).     

Estrogen receptor beta selective ligands: discovery and SAR of novel heterocyclic ligands

A series of ligands with varying heterocyclic cores and substituents that display a range of selectivity’s (up to >100x) for ER-β over ER- are reported.     

5,7-Diphenyl-3-ureidohexahydroazepin-2-ones as Cholecystokinin-B receptor ligands

A series of 5,7-diphenyl-3-ureidohexahydroazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 2,4-diphenylcyclohexanone as a key step. SAR studies revealed the importance of the 5-aryl group for high and selective CCK-B receptor affinity, as illustrated in compound (−)-10i (CCK-B IC₅₀ = 6.8 nM).     

Promising core structure for nuclear receptor ligands: design and synthesis of novel estrogen receptor ligands based on diphenylamine skeleton

Novel diphenylamine-type estrogen receptor ligands were designed and synthesized, and their biological activities were evaluated by means of binding assays for estrogen receptor-alpha and -beta and cell proliferation assay using MCF-7 cells. Compounds 4f, 11b, 12c, and 8 showed moderate estrogenic activities. We propose that the diphenylamine skeleton may be a privileged structure for various nuclear receptor ligands, including RAR, RXR, and AR ligands.     

Estrogen receptor ligands. Part 1: The discovery of flavanoids with subtype selectivity

A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.     

Estrogen receptor ligands. Part 16: 2-Aryl indoles as highly subtype selective ligands for ERalpha

A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.     

Design and synthesis of pyrazolopyridine derivatives as sphingosine 1-phosphate receptor 2 ligands

Eleven new sphingosine 1-phosphate receptor 2 (S1PR2) ligands were synthesized by modifying lead compound N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazine-1-carboxamide (JTE-013) and their binding affinities toward S1PRs were determined in vitro using [³²P]S1P and cell membranes expressing recombinant human S1PRs. Among these ligands, 35a (IC₅₀?=?29.1?±?2.6?nM) and 35b (IC₅₀?=?56.5?±?4.0?nM) exhibit binding potency toward S1PR2 comparable to JTE-013 (IC₅₀?=?58.4?±?7.4?nM) with good selectivity for S1PR2 over the other S1PRs (IC₅₀?>?1000?nM). Further optimization of these analogues may identify additional and more potent and selective compounds targeting S1PR2.     

Substituted 3-(2-benzoxazyl)-benzimidazol-2-(1H)-ones: a new class of GABA(A) brain receptor ligands

A novel class of potent benzodiazepine receptor (BZR) ligands has been designed and synthesized aided by molecular modeling of known benzodiazepine ligands such as CGS-8216 and the use of known pharmacophore models.     

Estrogen receptor ligands. Part 6: Synthesis and binding affinity of dihydrobenzodithiins

Dihydrobenzodithiin compounds (1-6) were prepared to explore the expansion of the dihydrobenzoxathiin lead compounds I-III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, however, they lacked the in vivo antagonism/agonism activity exhibited by the lead class in an immature rat uterine growth model.     

Estrogen receptor ligands. Part 3: The SAR of dihydrobenzoxathiin SERMs

A series of 3-alkyl, 3-cycloalkyl, and 3-heteroaryl dihydrobenzoxathiin analogs 1 were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. In general, the compounds were found to exhibit a high degree of selectivity for ER alpha over ER beta, but were less potent than the original lead compound 1a in the inhibition of estradiol-driven uterine proliferation.     

Nonsteroidal progesterone receptor ligands (I): synthesis and SAR of new tetrahydronaphthofuranone derivatives

We have synthesized a series of nonsteroidal progesterone receptor (PR) ligands, tetrahydronaphthofuranones, structurally based on the fungal metabolite PF1092C. Structure-activity relationship studies revealed that substituents at the 6- and 7-positions were critical for PR binding affinity and for agonist or antagonist activity. Compounds in this series, exemplified by 19i, exhibited high affinity and high specificity for PR over other steroid hormone receptors and acted as selective PR antagonists. Further modification of PF1092C may generate compounds of potential pharmacological interest.     

Estrogen receptor ligands. Part 11: Synthesis and activity of isochromans and isothiochromans

The ring oxygen and sulfur analogs of lasofoxifene, 1a and 1b, were synthesized in an attempt to impart ERalpha selectivity, as found in the closely related dihydrobenzoxathiin compound I, recently discovered in these laboratories. The resulting isochroman and isothiochroman compounds were found to exhibit equipotent binding affinities to the ER isoforms and were less active in the inhibition of estradiol-triggered uterine growth when compared to I and lasofoxifene.     

Fluorescent ligands for the histamine H2 receptor: synthesis and preliminary characterization

3-[3-(Piperidinomethyl)phenoxy]alkyl, N-cyano-N′-[ω-[3-(1-piperidinylmethyl)phenoxy]alkyl]guanidine and 2-(5-methyl-4-imidazolyl)methyl thioethyl derivatives containing fluorescent functionalities were synthesized and the histamine H₂ receptor affinity was evaluated using the H₂ antagonist [¹²⁵I]-aminopotentidine. The compounds exhibited weak to potent H₂ receptor affinity with pK_i values ranging from <4 to 8.85. The highest H₂ receptor affinity was observed for N-cyano-N′-[ω-[3-(1-piperidinylmethyl)phenoxy]alkyl]guanidines substituted with methylanthranilate (13), cyanoindolizine (6) and cyanoisoindole (11) moieties via an ethyl or propyl linker.     

Piperidinylpyrroles: design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands

Piperidinylpyrroles of type 3 were synthesized through a modified Paal-Knorr reaction. For the introduction of pyrrole-substituents high yielding transformations including Sonogashira cross-coupling reactions were utilized. Employment of the reagent TosMIC gave access to the regioisomeric oxazolyl derivatives 7 and 11 which showed the highest dopamine D4 receptor binding of the series investigated.     

Estrogen receptor ligands. Part 4: The SAR of the syn-dihydrobenzoxathiin SERAMs

A series of estrogen receptor ligands based on a dihydrobenzoxathiin scaffold is described and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. The most active analogue, 22, was found to be 40-fold ERalpha selective in a competitive binding assay, and 22 demonstrated very potent in vivo antagonism of estradiol driven proliferation in an immature rat uterine weight gain assay.     

ORL1 receptor ligands: structure-activity relationships of 8-cycloalkyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-ones

We have investigated 8-cycloalkyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-o nes as ligands for the ORL1 receptor. These unsophisticated, achiral compounds show remarkable affinity for the ORL1 receptor. Optimizing for selectivity we show that the maximum of affinity and selectivity versus the other opioid receptors is achieved for 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-o ne 2e and 8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5] decan-4-one 2q. The identified compounds (2e, 2q) are more or less equipotent to the natural ligand itself, both in the binding assay and in the functional GTPgammaS assay.