Bevirimat (3-O-(3',3'-dimethylsuccinyl) betulinic acid or MPC-4326 or PA-457) potently inhibits replication of both WT and drug-resistant HIV-1 isolates and demonstrate that the compound acts by disrupting a late step in Gag processing involving conversion of the capsid precursor (p25) to mature capsid protein (p24). Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has been in phase 2 trial for the treatment of HIV infections. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients. The demonstration of an antiviral effect following a single oral dose of bevirimat validates maturation inhibition as a potential target for antiretroviral therapeutics in humans.

Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. Basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy. Basimglurant is being under development by Roche for the treatment of treatment-resistant depression (as an adjunct). It is in phase II clinical trials for this indication.

Andrographolide, a diterpenoid, is known for its anti-inflammatory effects. It can be isolated from various plants of the genus Andrographis, commonly known as 'creat'. Andrographolide has been tested for its anti-inflammatory effects in various stressful conditions, such as ischemia, pyrogenesis, arthritis, hepatic or neural toxicity, carcinoma, and oxidative stress. Apart from its anti-inflammatory effects, andrographolide also exhibits immunomodulatory effects by effectively enhancing cytotoxic T cells, natural killer (NK) cells, phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). The properties of andrographolide, such as its ability to induce apoptosis of cancer cells and inhibition of DTH, its anti-oxidative and cytoprotective effect, and its ability to enhance CTLs and NK cell activation makes it a potent antiviral agent. Andrographolide inhibited the growth of human breast, prostate, and hepatoma tumors. Andrographolide could be a potent anticancer agent when used in combination with other chemotherapeutic agents.

Acolbifene, the active metabolite of EM-800, was identified as a pure antagonist that acts on both activation domains of the ERs. It is in Phase III clinical trials for the prevention of breast cancer and vasomotor symptoms (Hot flush) in postmenopausal women. Most commonly reported adverse events included irregular menses, leg/muscle cramps, diarrhea, and hot flashes. No serious adverse events were reported.

The novel compounds clamikalant (HMR 1883) or its sodium salt HMR 1098) have been shown to block selectively Kir6.2/SUR1-composed K(ATP) channels. Clamikalant is under development by Aventis Pharma (formerly Hoechst Marion Roussel) for the potential treatment of heart arrest and ventricular arrhythmias. Nevertheless, clamikalant and its sodium salt did not pass the clinical trials

R-etodolac (SDX-101) is the non-cyclooxygenase 2-inhibiting R-enantiomer of the non-steroid anti-inflammatory drug etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid). The absolute configuration of the enantiomer is R-(-)-etodolac. R-etodolac specifically bound retinoid X receptor (RXRalpha), inhibited RXRalpha transcriptional activity, and induced its degradation by a ubiquitin and proteasome-dependent pathway. In addition R-etodolac can disrupt the beta-catenin signaling pathway. R-etodolac exerts antineoplastic properties. R-etodolac was in phase 2 studies for the treatment of hematologic malignancies however development was discontinued.

GV 150526A (gavestinel) is an investigational drug for a neuroprotective therapy of acute ischemic stroke within 6 hours of symptom onset. It is a potent and selective non-competitive antagonist at the glycine site of the N-methyl-D-aspartate receptor (NMDA) which reduces infarct volume in experimental stroke models. Gavestinel acts at the strychnine-insensitive glycine binding site of the NMDA receptor-channel complex with nanomolar affinity (pKi = 8.5), coupled with high glutamate receptor selectivity. Gavestinel displays higher than 1000-fold selectivity over NMDA, AMPA and kainate binding sites and is orally bioavailable and active in vivo. GV 150526A inhibited convulsions induced by NMDA in mice, when administered by both IV and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The safety and efficacy of GV150526 were studied in two phase III randomized placebo-controlled clinical trials of acute ischemic stroke patients within 6 h from onset [The Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas Trials] sponsored by GlaxoSmithKline. The results of these trials suggested that gavestinel was not of substantial benefit or harm to patients with primary intracerebral hemorrhage.

18alpha-Glycyrrhetinic acid (18-GA), a derivative of enoxolone, is used to inhibit gap junctions and furthermore, it has anti-proliferative properties against various cancer types by affecting the cell cycle proteins. 18alpha-Glycyrrhetinic acid, is a non-selective inhibitor of 11beta-hydroxysteroid dehydrogenases isozymes and results in increased whole body insulin sensitivity and decreased glucose production.

Cucurbitacin I (JSI-124) is a novel selective triterpenoid that acts as a potent inhibitor of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway with anti-proliferative and anti-tumor properties. Cucurbitacin I specifically suppresses levels of tyrosine phosphorylated STAT3 in v-Src-transformed NIH 3T3 cells and in A549 cells (IC50 = 500 nM) resulting in inhibition of STAT3 DNA binding and reduced STAT3-mediated gene transcription. It also suppresses JAK2 phosphorylation but does not affect Src, ERK, JNK or Akt. In nude mice, cucurbitacin I (1 mg/kg/day) suppressed the growth of various tumors expressing constitutively active STAT3.1 It promotes the differentiation of dendritic cells and macrophages and enhances the effect of cancer immunotherapy. Cucurbitacin I (1 µM for 2 hours) reduced clonogenicity of nasopharyngeal carcinoma cells in vitro and suppresses tumor growth in mice (1.3 mg/kg).

Olesoxime (TRO19622) a small-molecule with a cholesterol-like structure has remarkable neuroprotective properties for motor neurons in cell culture and in rodents. The biopharmaceutical company Trophos initially developed this compound. This medicine is in phase II clinical trial in treating spinal muscular atrophy and in phase I for patients with stable relapsing remitting multiple sclerosis. This drug was also investigated in phase III clinical trial for amyotrophic lateral sclerosis, but it did not demonstrate a significant increase in survival versus placebo and that study was discontinued. Preclinical studies have demonstrated that the olesoxime promoted the function and survival of neurons and other cell types under disease-relevant stress conditions through interactions with the mitochondrial permeability transition pore (mPTP).