A survey of core replacements in indole-based HIV-1 attachment inhibitors.

Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3).

Inhibitors of HIV-1 attachment. Part 3: A preliminary survey of the effect of structural variation of the benzamide moiety on antiviral activity.

1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.

Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns.

The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype.

N-(5-chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as gamma-secretase inhibitors.

A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.

Structure-activity relationships of SERMs optimized for uterine antagonism and ovarian safety.

Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.

A selective estrogen receptor modulator for the treatment of hot flushes.

A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus.

A selective estrogen receptor modulator designed for the treatment of uterine leiomyoma with unique tissue specificity for uterus and ovaries in rats.

The design of a novel selective estrogen receptor modulator (SERM) for the potential treatment of uterine leiomyoma is described. 16 (LY2066948-HCl) binds with high affinity to estrogen receptors alpha and beta (ERalpha and ERbeta, respectively) and is a potent uterine antagonist with minimal effects on the ovaries as determined by serum biomarkers and histologic evaluation.

A new selective estrogen receptor modulator with potent uterine antagonist activity, agonist activity in bone, and minimal ovarian stimulation.

The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective estrogen receptor modulator compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors and has potent estrogen antagonist activity in human uterine and breast cancer cells.

Benzothiophene and naphthalene derived constrained SERMs.

For selective estrogen receptor modulators (SERMs), the orientation of the basic side chain relative to the SERM core has a significant impact on function. The synthesis and biological evaluation of two series of SERMs are disclosed, where the ligand side chain is constrained to adopt a defined orientation. Compounds where the side chain is forced into the plane of the SERM core have a different profile compared to those compounds where the side chain is pseudo-orthogonal, particularly with regard to antagonism of estradiol action on an Ishikawa uterine cell line.

Hydroxytriamides as potent gamma-secretase inhibitors.

Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.

Estrogen receptor modulators: relationships of ligand structure, receptor affinity and functional activity.

The estrogen receptor is a regulator of a wide range of physiological functions, including the female reproductive system, in addition to bone, cardiovascular and CNS function. ER ligands have been approved for the treatment of menopausal symptoms, breast cancer and osteoporosis, however the search continues for new modulators of ER function with improved properties. Progress in medicinal chemistry programs has resulted in the identification of structurally diverse molecules with unique biological properties.

Discovery of 4-benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions.

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption.

Tetrahydroquinoline-based selective estrogen receptor modulators (SERMs).

A new series of estrogen receptor ligands based on a 6-hydroxy-tetrahydroquinoline scaffold is described, in addition to their binding affinity and functional activity in MCF-7 cells. Several 1,2-disubstituted tetrahydroquinolines bearing a basic side chain were shown to be high affinity ligands and antagonists in the MCF-7 proliferation assay. Compounds lacking the basic side chain were agonists in the MCF-7 assay.

Inhibitors of Abeta production: solid-phase synthesis and SAR of alpha-hydroxycarbonyl derivatives.

Inhibitors of amyloid-beta (Abeta) protein production have been widely pursued as a potential treatment for Alzheimer's disease. Following the identification of a 5 microM screening hit, SAR was initiated using solid-phase synthetic techniques. Two series of alpha-hydroxy esters and ketones which are sub-micromolar inhibitors of Abeta production were identified.