BMS-986251 / BMS - LARVOL DELTA

Adventures in the synthesis of a complex pharmaceutical candidate enabled by novel reactions (ACS-Fall 2024) - "BMS-986251, a clinical RORgT inverse agonist, is a potential treatment for many immunological disorders...The optimized route is convergent and features a 6-setp synthesis for the core and a 7 step synthesis for the sidechain with complete enatio-control. The synthesis highlights include: a novel DKR to set the stereochemistry in the sidechain, one-step installation of the perfluoro iso-Pr moiety through a radical mechanism, and leverages a novel diastereoselective annulation to build the pyrrolidine ring."

Immunology

Adventures in the synthesis of a complex pharmaceutical candidate enabled by novel reactions (ACS-Sp 2022) - "BMS-986251 is a potent and selective Retinoic Acid-Related Orphan Receptor-gt (RORgt) discovered and developed at Bristol Myers Squibb...This presentation will discuss the process solutions implemented to enable early scale up activities. The advancement of a highly stereoselective synthesis to support long-term program deliverables will be described with an emphasis on the development of new reactions for the installation of the perfluoro-iso-propyl group and the chiral heterocyclic core."

Thymic lymphomas in a 6-Month rasH2-Tg mouse carcinogenicity study with the RORγt Inverse Agonist, BMS-986251. (PubMed, Toxicol Sci) - "Since lymphoid hyperplasia may represent a pre-neoplastic change, a no-effect dose for potential tumor induction was not identified in this study. These results led to the discontinuation of BMS-986251 and underscores the challenges in targeting RORγt for drug development."

Journal • Preclinical • Hematological Malignancies • Immunology • Lymphoma • Oncology

Retinoic acid-related orphan receptor gamma (RORγ) inverse agonists/antagonists for the treatment of inflammatory diseases - where are we presently? (PubMed, Expert Opin Drug Discov) - "The main reasons were lack of efficacy (topical) or safety signals (oral) as well as, amongst other things, thymic lymphomas as seen with BMS-986251 in a preclinical study and liver enzyme elevations in humans with VTP-43742. Possibilities to mitigate these risks could be the use of RORγt inverse agonists with different chemical structures not interfering with thymocytes maturation and no liver tox inducing properties. With few new frontrunners (e.g. ABBV-157 (cedirogant), BI 730357 or IMU-935) this is still an exciting time for this novel treatment approach."

Journal • Hematological Malignancies • Immunology • Inflammation • Lymphoma • Oncology • IL17A

A Study of Experimental Medication BMS-986251, Taken by Mouth, in Healthy Participants and Patients With Average to Very Serious Psoriasis (clinicaltrials.gov) - P1/2; N=192; Recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P1/2 trial • Ankylosing Spondylitis • Dermatology • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Inflammation • Inflammatory Arthritis • Inflammatory Bowel Disease • Non-alcoholic Steatohepatitis • Psoriasis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies • CRP • IL17A

A Study of Experimental Medication BMS-986251, Taken by Mouth, in Healthy Participants and Patients With Average to Very Serious Psoriasis (clinicaltrials.gov) - P1/2; N=38; Terminated; Sponsor: Bristol-Myers Squibb; N=192 ➔ 38; Trial completion date: Aug 2019 ➔ Jun 2018; Recruiting ➔ Terminated; Trial primary completion date: Aug 2019 ➔ Jun 2018; Adverse change in the risk/benefit

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Ankylosing Spondylitis • Dermatology • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Inflammatory Bowel Disease • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Psoriasis • Psoriatic Arthritis • Rheumatoid Arthritis • Seronegative Spondyloarthropathies • CRP • IL17A

Tricyclic-Carbocyclic RORγt Inverse Agonists-Discovery of BMS-986313. (PubMed, J Med Chem) - "SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1...In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1."

Journal • Dermatology • Immunology • Psoriasis

Annulation Reaction Enables the identification of an Exocyclic Amide Tricyclic Chemotype as Retinoic Acid Receptor-Related Orphan Receptor Gamma (RORγ/RORc) Inverse Agonists. (PubMed, Bioorg Med Chem Lett) - "One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed."

Journal • Immunology • IL17A

Synthesis of 1-(tert-Butyl) 4-Methyl (1R,2S,4R)-2-Methylcyclohexane-1,4-Dicarboxylate from Hagemann's tert-Butyl Ester for an Improved Synthesis of BMS-986251. (PubMed, J Org Chem) - "In addition, we describe a second generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical component.was instrumental in the generation of useful SAR during a RORt inverse agonist program. In addition, we describe a second generation synthesis of the clinical agent BMS-986251, using diester 1 as a critical component."

Journal

Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist. (PubMed, ACS Med Chem Lett) - "In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate."

Clinical • Journal • Immunology • IL17A • IL2