A Single Center, Phase I, Double-Blind, Placebo-Controlled Evaluation of the Safety, Tolerability, and Pharmacokinetics of Single Ascending Oral Doses of INV-101 in Healthy Male and Female Subjects

Single center, randomized, double-blinded, placebo-controlled, single ascending-dose study for the evaluation of the safety, tolerability, and PK following single oral doses of INV-101.

Start Date08 Sep 2020

Sponsor / Collaborator

Inversago Pharma, Inc.Startup

100 Clinical Results associated with NOS2 x CB1

100 Translational Medicine associated with NOS2 x CB1

0 Patents (Medical) associated with NOS2 x CB1

Literatures (Medical) associated with NOS2 x CB1

01 Jul 2021·Clinical and Translational MedicineQ2 · MEDICINE

CB₁R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome

Q2 · MEDICINE

ArticleOA

Author: Zawatsky, Charles N. ; Iyer, Malliga R. ; Kunos, George ; Park, Joshua K. ; Yokoyama, Tadafumi ; Jourdan, Tony ; O'Brien, Kevin J. ; Bodine, Steven P. ; Gahl, William A. ; Zuo, Mei Xing G. ; Mackie, Ken ; Malicdan, May Christine V. ; Coffey, Nathan J. ; Gochuico, Bernadette R. ; Abdalla, Jasmina ; Alimardanov, Asaf ; Cinar, Resat ; Huang, Junfeng ; Jay, Lindsey

AbstractHermansky–Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS‐1, leads to fatal adult‐onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1R system and inducible nitric oxide synthase (iNOS) for dual‐target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS‐PF patient‐derived lung fibroblasts, and bleomycin‐induced PF in pale ear mice (HPS1ep/ep). We found overexpression of CB1R and iNOS in fibrotic lungs of HPSPF patients and bleomycin‐infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin‐induced PF. Simultaneous targeting of CB1R and iNOS by MRI‐1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI‐1867 treatment abrogated bleomycin‐induced increases in lung levels of the profibrotic interleukin‐11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1R inhibition. Dual inhibition of CB1R and iNOS is an effective antifibrotic strategy for HPSPF.

01 Oct 2020·DiabetesQ1 · MEDICINE

Simultaneous Inhibition of Peripheral CB1R and iNOS Mitigates Obesity-Related Dyslipidemia Through Distinct Mechanisms

Q1 · MEDICINE

Article

Author: Vergès, Bruno ; Passilly-Degrace, Patricia ; Kunos, George ; Demizieux, Laurent ; Iyer, Malliga R. ; Leemput, Julia ; Cinar, Resat ; Degrace, Pascal ; Roger, Célia ; Muller, Tania ; Buch, Chloé ; Jourdan, Tony

Diabetic dyslipidemia, characterized by increased plasma triglycerides and decreased HDL cholesterol levels, is a major factor contributing to nonalcoholic steatohepatitis and cardiovascular risk in type 2 diabetes. Activation of the cannabinoid-1 receptor (CB1R) and activation of inducible nitric oxide synthase (iNOS) are associated with nonalcoholic steatohepatitis progression. Here, we tested whether dual-targeting inhibition of hepatic CB1R and iNOS improves diabetic dyslipidemia in mice with diet-induced obesity (DIO mice). DIO mice were treated for 14 days with (S)-MRI-1867, a peripherally restricted hybrid inhibitor of CB1R and iNOS. (R)-MRI-1867, the CB1R-inactive stereoisomer that retains iNOS inhibitory activity, and JD-5037, a peripherally restricted CB1R antagonist, were used to assess the relative contribution of the two targets to the effects of (S)-MRI-1867. (S)-MRI-1867 reduced hepatic steatosis and the rate of hepatic VLDL secretion, upregulated hepatic LDLR expression, and reduced the circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9). The decrease in VLDL secretion could be attributed to CB1R blockade, while the reduction of PCSK9 levels and the related increase in LDLR resulted from iNOS inhibition via an mTOR complex 1–dependent mechanism. In conclusion, this approach based on the concomitant inhibition of CB1R and iNOS represents a promising therapeutic strategy for the treatment of dyslipidemia.

01 Apr 2020·Pharmacology & TherapeuticsQ1 · MEDICINE

The therapeutic potential of second and third generation CB1R antagonists

Q1 · MEDICINE

Review

Author: Cinar, Resat ; Iyer, Malliga R ; Kunos, George

Endocannabinoids acting via CB₁ receptors (CB₁R) play a critical role in regulating energy homeostasis, which was the rationale for the pharmaceutical development of CB₁R antagonists for the treatment of obesity. Although the first-in-class CB₁R antagonist rimonabant proved to be effective in mitigating obesity and its multiple cardiometabolic complications, it was withdrawn from clinical use due to CNS-mediated neuropsychiatric side effects, which halted the further therapeutic development of the whole class of these compounds. Compared to the brain, CB₁Rs are expressed at low yet functional levels in peripheral organs involved in regulating energy homeostasis, including liver, skeletal muscle, adipose tissue and endocrine pancreas. In recent preclinical studies, selective targeting of these receptors by 'second generation' peripherally restricted CB₁R antagonists replicated the metabolic benefits of rimonabant in rodent models of obesity and diabetes without causing CNS-mediated side effects. Increased CB₁R activity also contributes to complex, multifactorial disorders such as various forms of tissue fibrosis, treatment of which may benefit from simultaneous engagement of more than one therapeutic target. Accordingly, novel 'third generation' hybrid inhibitors of peripheral CB₁R and inducible NO synthase were tested in mouse models of liver and pulmonary fibrosis where their antifibrotic efficacy was found to exceed the efficacy of drugs that inhibit only one of these targets. In this review, we will discuss the challenges and opportunities offered by second and third generation CB₁R antagonists and their potential therapeutic uses.

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