PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer

The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P₃ at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P₃ to form PtdIns(4,5)P₂. PtdIns(3,4,5)P₃ can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P₂. Interestingly, while PTEN is a bona fide tumour suppressor and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP, SHIP2 and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced PIPP expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although PIPP depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically, SHIP2 and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival. SHIP2 or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP, SHIP2 and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression.     

Structural and Theoretical Investigations of 3,4,5‐Triamino‐1,2,4‐Triazolium Salts

Reactions using the high nitrogen heterocycle 3,4,5‐triamino‐1,2,4‐triazole (guanazine) with strong acids (HNO₃, HClO₄, and “HN(NO₂)₂”) resulted in a family of highly stable salts. All of the salts were characterized using spectroscopic as well as single crystal X‐ray diffraction studies. The X‐ray structures were compared to that obtained from theoretical calculations (MP2/6‐311+G(d, p) level). Initial safety testing (impact, friction) was carried out on all of the new materials.     

SHIP2: Structure,Function and Inhibition

SHIP2 is a phosphatase that acts at the 5‐position of phosphatidylinositol 3,4,5‐trisphosphate. It is one of several enzymes that catalyse dephosphorylation at the 5‐position of phosphoinositides or inositol phosphates. SHIP2 has a confirmed role in opsismodysplasia, a disease of bone development, but also interacts with proteins involved in insulin signalling, cytoskeletal function (thus having an impact on endocytosis, adhesion, proliferation and apoptosis) and immune system function. The structure of three domains (constituting about 38 % of the protein) is known. Inhibitors of SHIP2 activity have been designed to interact with the catalytic domain with sub‐micromolar IC₅₀ values: these come from a range of structural classes and have been shown to have in vivo effects consistent with SHIP2 inhibition. Much remains unknown about the roles of SHIP2, and possible future directions for research are indicated.     

Chemistry and Pharmacology of Nicotinic Ligands Based on 6‐[5‐(Azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol (AMOP‐H‐OH) for Possible Use in Depression

AMOP‐H‐OH (sazetidine‐A; 6‐[5‐(azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol) and some sulfur‐bearing analogues were tested for their activities in vitro against human α4β2‐, α4β4‐, α3β4*‐ and α1*‐nicotinic acetylcholine receptors (nAChRs). AMOP‐H‐OH was also assessed in an antidepressant efficacy model. AMOP‐H‐OH and some of its analogues have high potency and selectivity for α4β2‐nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (α4)₃(β2)₂‐nAChRs. More prolonged exposure to AMOP‐H‐OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for α4β2‐nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2‐nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP‐H‐OH and some of its analogues have a set of binding sites on α4β2‐nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP‐H‐OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP‐H‐OH also has profound and high potency antidepressant‐like effects in the forced swim test. The net action of prolonged exposure to AMOP‐H‐OH or its analogues, as for nicotine, seems to be a selective decrease in α4β2‐nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.     

Discovery,Synthesis, and Optimization of Diarylisoxazole‐3‐carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

The mitochondrial permeability transition pore (mtPTP) is a Ca²⁺‐requiring mega‐channel which, under pathological conditions, leads to the deregulated release of Ca²⁺ and mitochondrial dysfunction, ultimately resulting in cell death. Although the mtPTP is a potential therapeutic target for many human pathologies, its potential as a drug target is currently unrealized. Herein we describe an optimization effort initiated around hit 1 , 5‐(3‐hydroxyphenyl)‐N‐(3,4,5‐trimethoxyphenyl)isoxazole‐3‐carboxamide, which was found to possess promising inhibitory activity against mitochondrial swelling (EC₅₀<0.39 μM ) and showed no interference on the inner mitochondrial membrane potential (rhodamine 123 uptake EC₅₀>100 μM ). This enabled the construction of a series of picomolar mtPTP inhibitors that also potently increase the calcium retention capacity of the mitochondria. Finally, the therapeutic potential and in vivo efficacy of one of the most potent analogues, N‐(3‐chloro‐2‐methylphenyl)‐5‐(4‐fluoro‐3‐hydroxyphenyl)isoxazole‐3‐carboxamide ( 60 ), was validated in a biologically relevant zebrafish model of collagen VI congenital muscular dystrophies.     

Synthesis and Characterization of 3,4,5‐Triamino‐1,2,4‐Triazolium 5‐Nitrotetrazolate

3,4,5‐Triamino‐1,2,4‐triazolium 5‐nitrotetrazolate ( 2 ) was synthesized in high yield from 3,4,5‐triamino‐1,2,4‐triazole (guanazine) ( 1 ) and ammonium 5‐nitrotetrazolate. The new compound 2 was characterized by vibrational (IR and Raman) and multinuclear NMR spectroscopy (¹H, ¹³C, ¹⁵N), elemental analysis and single crystal X‐ray diffraction (triclinic, P(‐1), a=0.7194(5), b=0.8215(5), c=0.8668(5) nm, α=75.307(5), β=70.054(5), γ=68.104(5)°, V=0.4421(5) nm³, Z=2, ϱ=1.722 g cm⁻¹, R₁=0.0519 [F>4σ(F)], wR₂(all data)=0.1154). The ¹⁵N NMR spectrum and X‐ray crystal structure (triclinic, P‐1, a=0.5578(5), b=0.6166(5), c=0.7395(5) nm, α=114.485(5)°, β=90.810(5)°, γ=97.846(5)°, V=0.2286(3) nm³, Z=2, ϱ=1.658 g cm⁻¹, R₁=0.0460 [F>4σ(F)], wR₂(all data)=0.1153) of 1 were also determined.     

Structural and Preliminary Explosive Property Characterizations of New 3,4,5‐Triamino‐1,2,4‐triazolium (Guanazinium) Salts

Two new highly stable energetic salts were synthesized in reasonable yield by using the high nitrogen‐content heterocycle 3,4,5‐triamino‐1,2,4‐triazole and resulting in its picrate and azotetrazolate salts. 3,4,5‐Triamino‐1,2,4‐triazolium picrate (1) and bis(3,4,5‐triamino‐1,2,4‐triazolium) 5,5′‐azotetrazolate (2) were characterized analytically and spectroscopically. X‐ray diffraction studies revealed that protonation takes place on the nitrogen N1 (crystallographically labelled as N2). The sensitivity of the compounds to shock and friction was also determined by standard BAM tests revealing a low sensitivity for both. B3LYP/6–31G(d, p) density functional (DFT) calculations were carried out to determine the enthalpy of combustion (Δ_cH (1) =−3737.8 kJ mol⁻¹, Δ_cH (2) =−4577.8 kJ mol⁻¹) and the standard enthalpy of formation (Δ_fH° (1) =−498.3 kJ mol⁻¹, (Δ_fH° (2) =+524.2 kJ mol⁻¹). The detonation pressures (P (1) =189×10⁸ Pa, P (2) =199×10⁸ Pa) and detonation velocities (D (1) =7015 m s⁻¹, D (2) =7683 m s⁻¹) were calculated using the program EXPLO5.     

Pharmacophore‐Based Design of Novel Oxadiazoles as Selective Sphingosine‐1‐phosphate (S1P) Receptor Agonists with in vivo Efficacy

Sphingosine‐1‐phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure–activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five‐membered heterocycles, and the use of diverse 2,2′‐disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P₁ agonist, N‐methyl‐N‐(4‐{5‐[2‐methyl‐2′‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 45 ), and a dual S1P_1,5 agonist, N‐methyl‐N‐(3‐{5‐[2′‐methyl‐2‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 49 ), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head‐to‐head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan‐S1P receptor agonist, S1P_1,5 agonist 49 demonstrated comparable efficacy while S1P₁‐selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.     

A DFT Study on the Structures and Energies of Isomers of 4‐Amino‐1,3‐dinitro‐1,2,4‐triazol‐5‐one‐2‐oxide: New High Energy Density Compounds

Isomers of 4‐amino‐1,3‐dinitrotriazol‐5‐one‐2‐oxide (ADNTONO) are of interest in the contest of insensitive explosives and were found to have true local energy minima at the DFT‐B3LYP/aug‐cc‐pVDZ level. The optimized structures, vibrational frequencies and thermodynamic values for triazol‐5‐one N‐oxides were obtained in their ground state. Kamlet‐Jacob equations were used to evaluate the performance properties. The detonation properties of ADNTONO (D=10.15 to 10.46 km s⁻¹, P=50.86 to 54.25 GPa) are higher compared with those of 1,1‐diamino‐2,2‐dinitroethylene (D=8.87 km s⁻¹, P=32.75 GPa), 5‐nitro‐1,2,4‐triazol‐3‐one (D=8.56 km s⁻¹, P=31.12 GPa), 1,2,4,5‐tetrazine‐3,6‐diamine‐1,4‐dioxide (D=8.78 km s⁻¹, P=31.0 GPa), 1‐amino‐3,4,5‐trinitropyrazole (D=9.31 km s⁻¹, P=40.13 GPa), 4,4′‐dinitro‐3,3′‐bifurazan (D=8.80 km s⁻¹, P=35.60 GPa) and 3,4‐bis(3‐nitrofurazan‐4‐yl)furoxan (D=9.25 km s⁻¹, P=39.54 GPa). The  NH₂ group(s) appears to be particularly promising area for investigation since it may lead to two desirable consequences of higher stability (insensitivity), higher density, and thus detonation velocity and pressure.     

(2,2‐Diphenyl‐[1,3]oxathiolan‐5‐ylmethyl)‐(3‐phenyl‐propyl)‐amine: a Potent and Selective 5‐HT1A Receptor Agonist

A selective 5‐HT _1A receptor agonist : A new series of ligands acting at 5‐HT_1A serotonin receptor were identified. Among them (2,2‐diphenyl‐[1,3]oxathiolan‐5‐yl‐methyl)‐(3‐phenyl‐propyl)amine (shown) possesses outstanding activity (pK_i=8.72, pD₂=7.67, E_max=85) and selectivity (5‐HT_1A/α_1D>150), and represents a new 5‐HT_1A agonist chemotype.

     

3,5‐Bis(benzylidene)‐4‐oxo‐1‐phosphonopiperidines and Related Diethyl Esters: Potent Cytotoxins with Multi‐Drug‐Resistance Reverting Properties

A series of 3,5‐bis(benzylidene)‐4‐piperidones 3 were converted into the corresponding 3,5‐bis(benzylidene)‐1‐phosphono‐4‐piperidones 5 via diethyl esters 4 . The analogues in series 4 and 5 displayed marked growth inhibitory properties toward human Molt 4/C8 and CEM T‐lymphocytes as well as murine leukemia L1210 cells. In general, the N‐phosphono compounds 5 , which are more hydrophilic than the analogues in series 3 and 4 , were the most potent cluster of cytotoxins, and, in particular, 3,5‐bis‐(2‐nitrobenzylidene)‐1‐phosphono‐4‐piperidone 5 g had an average IC₅₀ value of 34 nM toward the two T‐lymphocyte cell lines. Four of the compounds displayed potent cytotoxicity toward a panel of nearly 60 human tumor cell lines, and nanomolar IC₅₀ values were observed in a number of cases. The mode of action of 5 g includes the induction of apoptosis and inhibition of cellular respiration. Most of the members of series 4 as well as several analogues in series 5 are potent multi‐drug resistance (MDR) reverting compounds. Various correlations were noted between certain molecular features of series 4 and 5 and cytotoxic properties, affording some guidelines in expanding this study.     

Aryl Biphenyl‐3‐ylmethylpiperazines as 5‐HT7 Receptor Antagonists

The 5‐HT₇ receptor (5‐HT₇R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5‐HT₇R antagonist SB‐269970 exhibited antidepressant‐like activity, whereas systemic administration of the 5‐HT₇R agonist AS‐19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5‐HT₇R antagonists or agonists, aryl biphenyl‐3‐ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5‐HT₇R. Among the synthesized compounds, 1‐([2′‐methoxy‐(1,1′‐biphenyl)‐3‐yl]methyl)‐4‐(2‐methoxyphenyl)piperazine ( 28 ) was the best binder to the 5‐HT₇R (pK_i=7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5‐HT₇R over other serotonin receptor subtypes, such as 5‐HT₁R, 5‐HT₂R, 5‐HT₃R, and 5‐HT₆R. In a molecular modeling study, the 2‐methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.     

Discovery of α‐Substituted Imidazole‐4‐acetic Acid Analogues as a Novel Class of ρ1 γ‐Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone

The ρ‐containing γ‐aminobutyric acid type A receptors (GABA_ARs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABA_ARs are of interest. In this study, we demonstrate that the partial GABA_AR agonist imidazole‐4‐acetic acid (IAA) is able to penetrate the blood–brain barrier in vivo; we prepared a series of α‐ and N‐alkylated, as well as bicyclic analogues of IAA to explore the structure–activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l ‐histidine by an efficient minimal‐step synthesis, and their pharmacological properties were characterized at native rat GABA_ARs in a [³H]muscimol binding assay and at recombinant human α₁β₂γ_2S and ρ₁ GABA_ARs using the FLIPR? membrane potential assay. The (+)‐α‐methyl‐ and α‐cyclopropyl‐substituted IAA analogues ((+)‐ 6 a and 6 c , respectively) were identified as fairly potent antagonists of the ρ₁ GABA_AR that also displayed significant selectivity for this receptor over the α₁β₂γ_2S GABA_AR. Both 6 a and 6 c were shown to inhibit GABA‐induced relaxation of retinal arterioles from porcine eyes.     

Synthesis and Biological Evaluation of Imidazo[2,1‐b][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors

A series of imidazo[2,1‐b][1,3,4]thiadiazole‐linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti‐proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)‐5‐fluoro‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)‐imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), 11 ((E)‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), and 15 ((E)‐6‐chloro‐3‐((6‐phenyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one) exhibited potent anti‐proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G₂/M phase, inhibition of tubulin assembly, and increased cyclin‐B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC₅₀ range of 1.1–1.6 μM , and inhibited tubulin polymerization with an IC₅₀ value (0.15 μM ) lower than that of combretastatin A‐4 (1.16 μM ). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin.     

5‐(Piperidin‐4‐yl)‐3‐Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ‐Aminobutyric Acid Type A Receptor Binding Site

A series of bioisosteric N₁‐ and N₂‐substituted 5‐(piperidin‐4‐yl)‐3‐hydroxypyrazole analogues of the partial GABA_AR agonists 4‐PIOL and 4‐PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3‐hydroxypyrazole analogue of 4‐PIOL ( 2 a ; IC₅₀～300 μM ) is a weak antagonist at the α₁β₂γ₂ GABA_AR, whereas substituting the N₁‐ or N₂‐position with alkyl or aryl substituents resulted in antagonists with binding affinities in the high nanomolar to low micromolar range at native rat GABA_ARs. Docking studies using a α₁β₂γ₂ GABA_AR homology model along with the obtained SAR indicate that the N₁‐substituted analogues of 4‐PIOL and 4‐PHP, 2 a – k , and previously reported 3‐substituted 4‐PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N₂‐substituted analogues of 4‐PIOL and 4‐PHP, 3 b – k , are suggested to flip 180° thereby adapting to the binding pocket and addressing a cavity situated above the core scaffold.     

Synthesis and Biological Evaluation of 1‐Methyl‐1H‐indole–Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors

A series of 1‐methyl‐1H‐indole–pyrazoline hybrids were designed, synthesized, and biologically evaluated as potential tubulin polymerization inhibitors. Among them, compound e19 [5‐(5‐bromo‐1‐methyl‐1H‐indol‐3‐yl)‐3‐(3,4,5‐trimethoxyphenyl)‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide] showed the most potent inhibitory effect on tubulin assembly (IC₅₀=2.12 μm ) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC₅₀ values of 0.21–0.31 μm ). Further studies confirmed that compound e19 can induce HeLa cell apoptosis, cause cell‐cycle arrest in G₂/M phase, and disrupt the cellular microtubule network. These studies, along with molecular docking and 3D‐QSAR modeling, provide an important basis for further optimization of compound e19 as a potential anticancer agent.     

Design,Synthesis, and Structure–Activity Relationships of 3,4,5‐Trisubstituted 4,5‐Dihydro‐1,2,4‐oxadiazoles as TGR5 Agonists

Given its role in the mediation of energy and glucose homeostasis, the G‐protein‐coupled bile acid receptor 1 (TGR5) is considered a potential target for the treatment of type 2 diabetes mellitus and other metabolic disorders. By thorough analysis of diverse structures of published TGR5 agonists, a hypothetical ligand‐based pharmacophore model was built, and a new class of potent TGR5 agonists, based on the novel 3,4,5‐trisubstituted 4,5‐dihydro‐1,2,4‐oxadiazole core, was discovered by rational design. Three distinct synthetic methods for constructing 4,5‐dihydro‐1,2,4‐oxadiazoles and extensive structure–activity relationship studies are reported herein. Compound (R)‐ 54 n , the structure of which was determined by single‐crystal X‐ray diffraction and quantum chemical solid‐state TDDFT‐ECD calculations, showed the best potency, with an EC₅₀ value of 1.4 nM toward hTGR5. Its favorable properties in vitro warrant further investigation.     

Potent Inhibition of Acid Sphingomyelinase by Phosphoinositide Analogues

The different mammalian sphingomyelinases are involved in cell regulation, apoptosis and inflammatory events. Recent reports suggest pharmacological potential especially for inhibitors of the acid sphingomyelinase. Phosphatidyl inositol‐3,5bisphosphate (PtdIns3,5P₂) is the most potent selective acid sphingomyelinase inhibitor known to date. In the present study, we synthesized analogues of PtdIns3,5P₂ for initial structure–activity‐relationship (SAR) studies. We identified an inhibitor that is easy to synthesize, that has superior chemical and biophysical properties when compared to PtdIns3,5P₂ and that should be stable against virtually all phospholipases. Last but not least, the new inhibitor partially protected cells from dexamethasone‐induced cell death.     

Recent Developments of 19‐Nor‐1,25‐dihydroxyvitamin D3 Analogues

The vitamin D hormone, 1α,25‐dihydroxyvitamin D₃ [1,25‐(OH)₂D₃], exerts its hormonal effects predominantly on intestine, bone, and kidney, where it plays a crucial role in calcium and phosphorus homeostasis and bone mineralization. In addition to its classical actions, 1,25(OH)₂D₃ exerts pleiotropic effects in a wide variety of target tissues and cell types, often in an autocrine/paracrine fashion. These biological activities of 1,25(OH)₂D₃ have suggested a multitude of potential therapeutic applications for the vitamin D hormone in the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). However, the calcemic effects induced by 1,25(OH)₂D₃—hypercalcemia, increased bone resorption, and soft tissue calcification—limit the use of the natural ligand in these clinical applications. Therefore, numerous 1,25(OH)₂D₃ analogues have been synthesized with the intent of producing therapeutic agents devoid of hypercalcemic and hyperphosphatemic side effects. To this aim, much attention has been focused on the development of 19‐nor‐vitamin D₃ derivatives that lack the ring‐A exocyclic methylene group (C19). In this review, the 19‐nor‐1,25(OH)₂D₃ analogues are classified according to modifications made at the A‐ring, the side chain, or both the A‐ring and side chain, as well as other positions. The biological activities of these 19‐nor‐1,25(OH)₂D₃ analogues are summarized and their structure–activity relationships and binding features with the vitamin D receptor (VDR) are discussed.