Delving into the Latest Updates on BMS-986144 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

NS3/NS4A

Action

inhibitors

Mechanism

NS3/NS4A inhibitors(Hepatitis C virus serine protease, NS3/NS4A inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System Disorders

Active Indication-

Inactive Indication

Hepatitis C

Originator Organization

Bristol Myers Squibb Co.

Active Organization-

Inactive Organization

Bristol Myers Squibb Co.

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC40H51F4N5O9S

InChIKeyIJNUZTYJYYUXSD-YTEVSDLFSA-N

CAS Registry1606150-08-6

Author: Pulicharla, Nagalakshmi ; Meanwell, Nicholas A. ; McPhee, Fiona ; Sinha, Sarmistha ; Zheng, Barbara ; Fang, Hua ; Sivaprasad, Sankar ; Rampulla, Richard ; D’Andrea, Stanley ; Scola, Paul M. ; Kumar, Amit ; Baratam, Venkata Rao ; Sun, Li-Qiang ; Mosure, Kathy ; Kandhasamy, Sarkunam ; Wang, Ying-Kai ; Loy, James ; Jenkins, Susan ; Puttaswamy, Sunitha ; Reddy, Subba ; Chen, Chaoqun ; Rendunchintala, Kishore ; Desai, Salil ; Mathur, Arvind ; Trivedi, Ravi ; Anumula, Rushith ; Hiebert, Sheldon ; Mull, Eric ; Zvyaga, Tatyana A. ; Bowsher, Michael ; Vishwakrishnan, Sureshbabu ; Ghosh, Kaushik ; Gillis, Eric ; Rajamani, Ramkumar ; Falk, Paul ; Tagore, Debarati M. ; Rao, Abhijith

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF₃Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD₃O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD₃O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH₃O prototype.

100 Deals associated with BMS-986144

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