ABSTRACT
A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, ß and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARß. The potent and selective RARγ antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARα-mediated adverse effects.
Subject(s)
Drug Design , Osteoarthritis/drug therapy , Pain/drug therapy , Piperazines/pharmacology , Pyrazoles/pharmacology , Receptors, Retinoic Acid/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , Retinoic Acid Receptor gammaABSTRACT
Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell- and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure-activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiophene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen.
Subject(s)
Bone Matrix/drug effects , Collagen/metabolism , Femur/drug effects , Raloxifene Hydrochloride/pharmacology , Animals , Bone Matrix/metabolism , Collagen/chemistry , Dogs , Durapatite/chemistry , Femur/metabolism , Hydrophobic and Hydrophilic Interactions , Male , Piperidines/chemistry , Polylysine/chemistry , Polylysine/metabolism , Protein Binding , Raloxifene Hydrochloride/metabolism , Receptors, Estrogen/metabolism , Static Electricity , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor ß (TRß) agonists is described. Compounds with >50× binding selectivity for TRß over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.
Subject(s)
Acetates/pharmacology , Drug Design , Indoles/pharmacology , Thyroid Hormone Receptors beta/agonists , Acetates/chemical synthesis , Acetates/chemistry , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Benzopyrans are selective estrogen receptor (ER) beta agonists (SERBAs), which bind the ER receptor subtypes alpha and beta in opposite orientations. We have used structure based drug design to show that this unique phenomena can be exploited via substitution at the 8-position of the benzopyran A-ring to disrupt binding to ERalpha, thus improving ERbeta subtype selectivity. X-ray cocrystal structures with ERalpha and ERbeta are supportive of this approach to improve selectivity in this structural class.
Subject(s)
Benzopyrans/pharmacology , Estrogen Receptor beta/agonists , Benzopyrans/chemistry , Crystallography, X-Ray , Ligands , Models, MolecularABSTRACT
Benzopyrans are selective estrogen receptor (ER) beta agonists (SERBAs), which bind the ER subtypes alpha and beta in opposite orientations. Here we describe the syntheses of cyclopentanone and cyclohexanone intermediates for SAR studies of the C-ring on the benzopyran scaffold. Modification of the C-ring disrupts binding to ERalpha, thus improving ERbeta selectivity up to 100-fold. X-ray cocrystal structures confirm previously observed binding modes.
Subject(s)
Benzopyrans/pharmacology , Chemistry, Pharmaceutical/methods , Cyclohexanones/chemical synthesis , Cyclopentanes/chemical synthesis , Estrogen Receptor beta/agonists , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Animals , Benzopyrans/chemistry , Crystallography, X-Ray/methods , Cyclohexanones/pharmacology , Cyclopentanes/pharmacology , Drug Design , Humans , Ligands , Mice , Models, Chemical , Protein Binding , Structure-Activity RelationshipABSTRACT
Benzopyran selective estrogen receptor beta agonist-1 (SERBA-1) shows potent, selective binding and agonist function in estrogen receptor beta (ERbeta) in vitro assays. X-ray crystal structures of SERBA-1 in ERalpha and beta help explain observed beta-selectivity of this ligand. SERBA-1 in vivo demonstrates involution of the ventral prostate in CD-1 mice (ERbeta effect), while having no effect on gonadal hormone levels (ERalpha effect) at 10x the efficacious dose, consistent with in vitro properties of this molecule.
Subject(s)
Estrogen Receptor beta/agonists , Flavonoids/chemical synthesis , Prostatic Hyperplasia/drug therapy , Selective Estrogen Receptor Modulators/chemical synthesis , Animals , Binding Sites , Crystallography, X-Ray , Estrogen Receptor alpha/chemistry , Estrogen Receptor beta/chemistry , Estrogens , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Ligands , Male , Mice , Models, Molecular , Molecular Structure , Prostate/drug effects , Prostate/pathology , Prostatic Hyperplasia/pathology , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity RelationshipABSTRACT
Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Cell Line , Drug Screening Assays, Antitumor , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Female , Half-Life , Humans , In Vitro Techniques , Mice , Mice, Nude , Quantitative Structure-Activity Relationship , Rats , Rats, Inbred F344 , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, Heterologous , Umbilical Veins/cytology , Vascular Endothelial Growth Factor A/pharmacology , Vascular Endothelial Growth Factor A/physiologyABSTRACT
An increasingly competitive pharmaceutical market demands improvement in the efficiency and probability of drug candidate discovery. Usually these new drug candidates are targeted for oral administration, so a detailed understanding of the molecular-level properties that relate to optimal pharmacokinetics is a critical step toward improving the probability of selecting successful clinical candidates. Although the characteristics of druglike molecules have been previously discussed in the literature, the importance of this topic sustains a continued interest for additional perspective and further detailed statistical analyses. In this contribution, we approach the analysis from the perspective of profiling distinguishing features of orally administered drugs. We have compiled both structural and route-administration information for a total of 1729 marketed drugs to provide a solid basis for developing a new perspective on the characteristics of over 1000 orally administered drugs. The molecular properties and most commonly occurring structural elements are statistically analyzed to capture the differences between routes of administration, as well as between marketed drugs and SAR or clinical compounds. We find that, with respect to other routes of administration, oral drugs tend to be lighter and have fewer H-bond donors, acceptors, and rotatable bonds than drugs with other routes of administration. These differences are particularly pronounced when comparing the mean values for oral vs injectable drugs. We also demonstrate that the mean property values for oral drugs do not vary substantially with respect to launch date, suggesting that the range of acceptable oral properties is independent of synthetic complexity or targeted receptor. Finally, we note that, while these properties are descriptive of each class, they are not necessarily predictive of what class any particular drug will reside in, since there is significant overlap in the acceptable ranges found for each drug class.