Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278

3区 · 医学

Article

作者: Murphy, Brian J ; Lehman-McKeeman, Lois ; Cheng, Peter T W ; Sivaraman, Lakshmi ; Davis, Myrtle ; Gill, Michael W

In a Phase 2 clinical trial, BMS-986020, a lysophosphatidic acid receptor-1 (LPA₁) antagonist, produced hepatobiliary toxicity (increased ALT, AST, and ALP; cholecystitis) and increases in plasma bile acids (BA). Nonclinical investigations conducted to identify a potential mechanism(s) for this toxicity examined BMS-986020 and two LPA₁ antagonists structurally distinct from BMS-986020 (BMS-986234 and BMS-986278). BMS-986020 inhibited hepatic BA efflux transporters BSEP (IC₅₀ 1.8 μM), MRP3 (IC₅₀ 22 μM), and MRP4 (IC₅₀ 6.2 μM) and inhibited BA canalicular efflux in human hepatocytes (68% at 10 μM). BMS-986020 inhibited mitochondrial function (basal and maximal respiration, ATP production, and spare capacity) in human hepatocytes and cholangiocytes at ≥10 μM and inhibited phospholipid efflux in human hepatocytes (MDR3 IC₅₀ 7.5 μM). A quantitative systems toxicology analysis (DILIsym®), considering pharmacokinetics, BA homeostasis, mitochondrial function, oxidative phosphorylation, and reactive intermediates performed for BMS-986020 recapitulated clinical findings ascribing the effects to BA transporter and mitochondrial electron transport chain inhibition. BMS-986234 and BMS-986278 minimally inhibited hepatic BA transporters (IC₅₀ ≥20 μM) and did not inhibit MDR3 activity (IC₅₀ >100 μM), nor did BMS-986234 inhibit BA efflux (≤50 μM) or mitochondrial function (≤30 μM) (BMS-986278 not evaluated). Multiple mechanisms may be involved in the clinical toxicity observed with BMS-986020. The data indicate that this toxicity was unrelated to LPA₁ antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA₁ antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278.

2011-09-01·Behavioural pharmacology4区 · 心理学

Cannabinergic aminoalkylindoles, including AM678=JWH018 found in ‘Spice’, examined using drug (Δ9-tetrahydrocannabinol) discrimination for rats

4区 · 心理学

Article

作者: Vadivel, Subramanian K. ; Jaerbe, Torbjoern U. C. ; Deng, Hongfen ; Makriyannis, Alexandros

We examined four different cannabinergic aminoalkylindole ligands, including one drug (AM678=JWH018) found in herbal 'Spice' concoctions, for their ability to substitute for Δ(9)-tetrahydrocannabinol (THC), and the ability of the cannabinoid receptor 1-selective antagonist/inverse agonist rimonabant to block the substitution, 30 and 90 min after intraperitoneal injection. Rats trained to discriminate the effects of vehicle from those produced by 3 mg/kg of THC were used. The order of potency was: AM5983≥AM678>AM2233>WIN55212-2 at both test intervals. AM5983 and AM678 appeared eight times more potent than THC, followed by AM2233 (about twice as potent as THC), and WIN55212-2 approximately THC at the 30-min test interval. The aminoalkylindoles showed reduced potency (i.e. an increased ED50 value) at the longer injection-to-test interval of 90 min compared with testing at 30 min. The rightward shifts by coadministration of rimonabant were approximately 8-fold to 12-fold for AM5983 and AM678, compared with an approximately 3-fold rightward shift for the WIN55212-2 curve. AM2233 (1.8 mg/kg) substitution was also blocked by 1 mg/kg of rimonabant. In conclusion, AM5983 and AM678=JWH018 are potent cannabimimetics derived from an aminoalkylindole template. WIN55212-2 seemed to interact differently with rimonabant, compared with either AM5983 or AM678, indicating potential differences in the mechanism(s) of action among cannabinergic aminoalkylindoles.

2011-03-01·The Journal of pharmacology and experimental therapeutics3区 · 医学

Pharmacokinetic and Pharmacodynamic Characterization of an Oral Lysophosphatidic Acid Type 1 Receptor-Selective Antagonist

3区 · 医学

Article

作者: Bain, G. ; Santini, A. M. ; Swaney, J. S. ; Seiders, T. J. ; Roppe, J. R. ; Hutchinson, J. H. ; Parr, T. A. ; Prasit, P. ; King, C. D. ; Broadhead, A. R. ; Lorrain, D. S. ; Evans, J. F. ; Chapman, C. ; Darlington, J. ; Stebbins, K. J. ; Ziff, J. ; Baccei, C. S. ; Correa, L. D. ; Lee, C.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through a family of at least six G protein-coupled receptors designated LPA₁₋₆. LPA type 1 receptor (LPA₁) exhibits widespread tissue distribution and regulates a variety of physiological and pathological cellular functions. Here, we evaluated the in vitro pharmacology, pharmacokinetic, and pharmacodynamic properties of the LPA₁-selective antagonist AM095 (sodium, {4'-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetate) and assessed the effects of AM095 in rodent models of lung and kidney fibrosis and dermal wound healing. In vitro, AM095 was a potent LPA₁ receptor antagonist because it inhibited GTPγS binding to Chinese hamster ovary (CHO) cell membranes overexpressing recombinant human or mouse LPA₁ with IC₅₀ values of 0.98 and 0.73 μM, respectively, and exhibited no LPA₁ agonism. In functional assays, AM095 inhibited LPA-driven chemotaxis of CHO cells overexpressing mouse LPA₁ (IC₅₀= 778 nM) and human A2058 melanoma cells (IC₅₀ = 233 nM). In vivo, we demonstrated that AM095: 1) had high oral bioavailability and a moderate half-life and was well tolerated at the doses tested in rats and dogs after oral and intravenous dosing, 2) dose-dependently reduced LPA-stimulated histamine release, 3) attenuated bleomycin-induced increases in collagen, protein, and inflammatory cell infiltration in bronchalveolar lavage fluid, and 4) decreased kidney fibrosis in a mouse unilateral ureteral obstruction model. Despite its antifibrotic activity, AM095 had no effect on normal wound healing after incisional and excisional wounding in rats. These data demonstrate that AM095 is an LPA₁ receptor antagonist with good oral exposure and antifibrotic activity in rodent models.

项与 AMS-III-1086 相关的新闻（医药）

2024-10-31

·Pharmaceutical Technology

Amgen earns higher revenues in Q3 2024, puts rare diseases in the spotlight

After splashing out $27.8bn for Horizon Therapeutics, Amgen is now seeing growth with drugs like Tepezza, Krystexxa, and Uplizna. Credits: Marlon Trottmann/Shutterstock.com Amgen has announced a total revenue of $8.5bn in Q3 2024, a 23% increase from a $6.9bn revenue in the same quarter of last year. The growth is driven by increased product sales by 24%, which included ten products delivering a sales growth in double-digits at minimum, as per a 30 October press release. These products included Repatha (evolocumab), Tezspire (tezepelumab-ekko), Evenity (romosozumab-aqqg), Tavneos (avacopan), and Blincyto (blinatumomab). A 17% growth was seen across Amgen’s innovative oncology portfolio as well as a 21% year over year (YOY) growth and a $1.2bn Q3 revenue was recorded across the rare disease portfolio, said Robert Bradway, chairman and CEO of Amgen in the 30 October conference call. The sales growth was driven by Tavneos, Tepezza (teprotumumab-trbw), Krystexxa (pegloticase) and Uplizna (inebilizumab-cdon), the latter three inflammatory treatments being acquired in October 2023 when Amgen bought Horizon Therapeutics for $27.8bn. The deal with the Horizon was finalised a month after both parties settled an administrative lawsuit with the US Federal Trade Commission (FTC) in September 2023. Following the acquisition of Horizon and the “mechanistic repositioning” of Tepezza, Amgen has launched multiple new projects in rare disease, said CSO Jay Bradner in the conference call. Amgen has since established a rare disease initiative with dedicated leadership in rare disease drug development and will ultimately “more than replenish the rare disease mid- and early-stage pipeline in the years to come”, Bradner added. See Also: Reeves’ 2024 budget promises life sciences investment Bladder cancer diagnoses to top 300,000 in major markets by 2033 Despite reaping success from the trio of rare disease products gained through Horizon, Amgen also whittled its rare disease portfolio by discontinuing the study of its lysophosphatidic acid receptor 1 (LPAR1) antagonist, fipaxalparant, in patients with idiopathic pulmonary fibrosis. The decision was made after a Phase II study of the drug failed to achieve any of its primary or secondary endpoints. The candidate is still being evaluated for the treatment of diffuse cutaneous systemic sclerosis. Amgen also expects to share topline data from the anticipated Phase II study of MariTide (maridebart cafraglutide) in late 2024. The Phase II study is being conducted in adults who are overweight or obese, with or without type 2 diabetes mellitus (T2D). The company is actively planning and on track to initiate a broad Phase III program in obesity, obesity-related conditions and T2D, said Bradner.