Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA1) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.

The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).

Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11ß-Hydroxysteroid Dehydrogenase Type 1 (11ß-HSD-1).

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.

Kathu Townlands: a high density Earlier Stone Age locality in the interior of South Africa.

Kathu Townlands is a high density Earlier Stone Age locality in the Northern Cape Province, South Africa. Here we present the first detailed information on this locality based on analysis of a sample of lithic material from excavations by P. Beaumont and field observations made in the course of fieldwork in 2013. The results confirm the remarkably high artefact density at Kathu Townlands and do not provide evidence consistent with high energy transport as a mechanism of site formation, suggesting that Kathu Townlands was the site of intensive exploitation of highly siliceous outcroppings of banded iron formation. The results presented here provide a first step towards understanding this complex locality and point to the need for further research and the importance of preserving this locality in the face of intensive and rapid development.

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11ß-Hydroxysteroid Dehydrogenase Type 1 (11ß-HSD-1).

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11ß-hydroxysteroid dehydrogenase-type 1 (11ß-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11ß-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

Landscape-scale variation in hominin tool use: Evidence from the Developed Oldowan.

The relationship between artifact manufacture, use, and discard in the Developed Oldowan is complex. Here we use digital-image-analysis techniques to investigate the intensity of reduction in single-platform cores of the Developed Oldowan of the Okote Member, Koobi Fora Formation. Data suggest that this method provides a more accurate measure of reduction intensity than previous applications of a unifacial-scraper model. Assemblages of single-platform cores excavated from extensive lateral exposures of the Okote Member provide insights into the relationship between raw-material availability and discard patterns. Variation in reduction intensity suggests that tools are not always discarded in patterns that would be predicted by the availability of raw material. Further, it appears that hominin transport decisions involved an assessment of the potential use-life of certain forms. Many aspects of Developed Oldowan technology conform to previously developed models of curated technologies.

Production of Enterotoxin by Yersinia Species Isolated from Milk.

A total of 70 Yersinia strains, comprising 40 Y. enterocolitica , 21 Y. intermedia , 8 Y. frederiksenii , and 1 Y. aldovae , isolated from Northern Ireland milk supplies, were tested for their ability to produce a heat-stable enterotoxin (YeST) when grown in a broth medium (incubated at 25°C for 48 h). Only Y. enterocolitica strains produced detectable levels of YeST. Of these, enterotoxin was detected with 76.9% and 55.5% of strains identified as biotypes 1 and 2, respectively, and YeST was produced by all serotypes tested. Enterotoxin was detected when a single Y. enterocolitica strain was grown at 25°C for 48 h in culture media containing either lactose, butterfat, or milk proteins at levels approximating those found in milk. Also, YeST was detected when this strain was grown in skimmed and full-fat UHT milks. When grown at 4°C for up to 7 d, however, enterotoxin was not detected in any of these media.