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.

Tanaproget (WAY-166989) is a nonsteroidal progesterone receptor agonist. It has been in Phase-II clinical trials as an oral contraceptive. The compound demonstrated a positive preclinical pharmacological profile in the treatment of endometriosis. The level of progesterone receptors in breast tumours can be used to guide the selection of endocrine therapies for breast cancer patients. Radiolabeled analogues of tanaproget have diagnostic potential as PET imaging agents for breast cancer.

BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. Bristol-Myers Squibb was developing BMS 690514, as an oral treatment for cancer. BMS-690514 had being in phase II for the treatment of breast cancer; non-small cell lung cancer, but later these studies were discontinued.

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.

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).

11-NOR-9-CARBOXY-DELTA9-TETRAHYDROCANNABINOL (THC-COOH) is the main the non-psychoactive metabolite of Delta9-Tetrahydrocannabinol. Being most abundant in bodily fluids, it has become an established marker of cannabis consumption in forensic, clinical and environmental analyses. Among the cannabinoids tested as potential inhibitors of the drug efflux transporter P-glycoprotein (Pgp), which is responsible for the multidrug-resistance of a tumour and normal cells, THC-COOH behaved as a substrate and was the most active in stimulating Pgp-dependent ATPase. It displayed analgesic and anti-inflammatory properties apparently by inhibiting cyclooxygenase and 5-lipoxygenase activities. THC-COOH was not an anxiolytic or anxiogenic drug but abolished the anxiogenic behavioral effect of Delta9-Tetrahydrocannabinol.

P-Cresol is an end product of protein breakdown and also it is a fermentation metabolite of tyrosine. The mechanisms underlying colonic carbohydrate and protein fermentation, responsible for the generation of p-cresol, are only partially understood. After absorption, the majority of p-cresol is conjugated to form p-cresyl sulphate. There is clear evidence, both in vitro and in vivo, that accumulation of conjugated fermentation metabolites is correlated with clinical important endpoints. In renal failure, the colonic generation rate of p-cresol is markedly elevated. Free p-cresol is an independent predictor for mortality in hemodialysis patients. The accumulation of p-cresol increases the cardiovascular risk of chronic kidney disease (CKD) patients. It was shown, that p-cresol l triggered autophagic renal proximal tubular cells death via JNK-mediated p62 accumulation and then activated caspase 8-dependent cell death pathway. Thus p-cresol can be considered as one of the key events causing progression of CKD, which might affect drug disposition in CKD cases.