ABSTRACT
The IQ Consortium NHP Reuse Working Group (WG) comprises members from 15 pharmaceutical and biotechnology companies. In 2020, the WG developed and distributed a detailed questionnaire on protein non-naïve NHP reuse to the WG member companies. The WG received responses from key stakeholders including principal investigators, facility managers, animal welfare officers and research scientists. This paper's content reflects the consolidated opinion of the WG members and the questionnaire responses on the subject of NHP reuse within nonclinical programs at all stages of research and development. Many of the pharmaceutical companies represented in the working group or participating in the questionnaire have already achieved some level of NHP reuse in their nonclinical programs, but the survey results suggested that there is significant potential to increase NHP reuse further and a need to understand the considerations involved in reuse more clearly. The WG has also focused carefully on the inherent concerns and risks of implementing protein non-naive NHP reuse and has evaluated the best methods of risk assessment and decision-making. This paper presents a discussion on the challenges and opportunities surrounding protein non-naïve NHP reuse and aims to stimulate further industry dialogue on the subject and provide guidance for pharmaceutical companies to establish roadmaps and decision trees enabling increased protein non-naïve NHP reuse. In addition, this paper represents a solid basis for collaborative engagement between pharmaceutical and biotechnology companies with contract research organizations (CROs) to discuss how the availability of protein non-naïve NHP within CROs can be better leveraged for their use within nonclinical studies.
Subject(s)
Drug Discovery , Primates , Animals , Drug Evaluation, Preclinical/methods , Drug Industry/methods , Pharmaceutical PreparationsABSTRACT
The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
Subject(s)
Arthritis, Experimental/drug therapy , Lysophospholipids/agonists , Sphingosine/analogs & derivatives , Structure-Activity Relationship , Administration, Oral , Animals , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Lymphocyte Count , Male , Rats, Inbred Lew , Receptors, Lysosphingolipid/agonists , Sphingosine/agonistsABSTRACT
In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.
Subject(s)
Organophosphates/pharmacology , Phenylacetates/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Arthritis, Experimental/drug therapy , Biological Availability , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Macaca fascicularis , Male , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Molecular Structure , Organophosphates/chemistry , Phenylacetates/chemistry , Prodrugs/pharmacokinetics , Protein Kinase Inhibitors/chemistry , Rats, Inbred Lew , Rats, Sprague-Dawley , Solubility , Structure-Activity RelationshipABSTRACT
An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).
Subject(s)
Arthritis, Experimental/drug therapy , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Receptors, Glucocorticoid/metabolism , Thiadiazoles/pharmacology , Animals , Blood/drug effects , Blood/metabolism , Chemistry Techniques, Synthetic , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors/chemistry , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Drug Stability , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Male , Rats, Inbred Lew , Receptors, Glucocorticoid/agonists , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacokinetics , Transcription Factor AP-1/metabolismABSTRACT
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.