Delving into the Latest Updates on BMS-955176 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target-

Mechanism

HIV replication inhibitors, Virus replication inhibitors

Therapeutic Areas

Immune System DiseasesInfectious DiseasesUrogenital Diseases

Active Indication

HIV Infections

Inactive Indication-

Originator Organization

Bristol Myers Squibb Co.

Active Organization

Bristol Myers Squibb Co.

Inactive Organization

GSK Plc

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure

Molecular FormulaC42H62N2O4S

InChIKeyXDMUFNNPLXHNKA-ZTESCHFWSA-N

CAS Registry1392312-45-6

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance.

22 Sep 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation

Q1 · MEDICINE

Article

Author: Hartz, Richard A. ; Hanumegowda, Umesh ; Benitex, Yulia ; Dicker, Ira ; Regueiro-Ren, Alicia ; Rahematpura, Sandhya ; Wu, Dauh-Rurng ; Protack, Tricia ; Hou, Xiaoping ; Mathur, Arvind ; Liu, Zheng ; Phillips, Thomas ; Park, Hyunsoo ; Zhang, Sharon ; Chen, Jie ; Sarjeant, Amy ; Santone, Kenneth S. ; Parker, Dawn ; Venables, Brian L. ; Kempson, James ; Rampulla, Richard ; Gupta, Anuradha ; Meanwell, Nicholas A. ; Li, Peng ; Li, Zhufang ; Swidorski, Jacob J. ; Chen, Yan ; Lin, Zeyu ; Jenkins, Susan ; Haskell, Roy ; Krystal, Mark ; Sin, Ny ; Sit, Sing-Yuen ; Cockett, Mark

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH₂F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.

01 Mar 2021·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Design and exploration of C-3 benzoic acid bioisosteres and alkyl replacements in the context of GSK3532795 (BMS-955176) that exhibit broad spectrum HIV-1 maturation inhibition

Q4 · MEDICINE

Article

Author: Dicker, Ira B ; Jenkins, Susan ; Beno, Brett R ; Parker, Dawn D ; Ng, Alicia ; Hanumegowda, Umesh ; Gupta, Anuradha ; Protack, Tricia ; Meanwell, Nicholas A ; Shanmugam, Yoganand ; Swidorski, Jacob J ; Regueiro-Ren, Alicia ; Krystal, Mark

GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp³-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.

100 Deals associated with BMS-955176

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External Link

KEGG	Wiki	ATC	Drug Bank
-	BMS-955176	-	DB15193

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Phase 2	ES	GSK Plc	12 May 2015
HIV Infections	Phase 2	DE	GSK Plc	12 May 2015
HIV Infections	Phase 2	CA	GSK Plc	12 May 2015
HIV Infections	Phase 2	ZA	GSK Plc	12 May 2015
HIV Infections	Phase 2	MX	GSK Plc	12 May 2015
HIV Infections	Phase 2	IT	GSK Plc	12 May 2015
HIV Infections	Phase 2	US	GSK Plc	12 May 2015
HIV Infections	Phase 2	GB	GSK Plc	12 May 2015
HIV Infections	Phase 2	CL	GSK Plc	12 May 2015
HIV Infections	Phase 2	AR	GSK Plc	12 May 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02415595 (Pubmed \| J Biol Chem) Manual	Phase 2	HIV Infections First line	206	tenofovir disoproxil fumarate+emtricitabine+GSK3532795	heycvhhwgl(vjeiybntun) = nykwewsyik klzbspdasu (sausxaoqss ) View more	Negative	23 Oct 2018
				tenofovir disoproxil fumarate+emtricitabine+efavirenz	heycvhhwgl(vjeiybntun) = lklhyklapz klzbspdasu (sausxaoqss ) View more
NCT02415595 (CTgov)	Phase 2	HIV Infections	210	FTC+TDF+BMS-955176 (BMS-955176/GSK3532795 60 mg + TDF/FTC)	gocrioxmdh(khfanmmlcf) = jjynmvzqrm dyyhwfjdtn (oksagxrlpj, ztowwbwpmz - nxsxujstch) View more	-	19 Sep 2018
				FTC+TDF+BMS-955176 (BMS-955176/GSK3532795 120 mg + TDF/FTC)	gocrioxmdh(khfanmmlcf) = fsmwsnuxsa dyyhwfjdtn (oksagxrlpj, sgzpkprwud - phkwyaqxlc) View more
NCT02386098 (CTgov)	Phase 2	HIV Infections	86	DTG+BMS-955176+ATV/r (Stage 1: BMS-955176 120 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD)	psnakpgfct(puokhytrrd) = mwvdxlaqxe dijtpojwlx (amyblamiul, mwgegyiidg - jpptuzmyct) View more	-	20 Aug 2018
				DTG+TDF+ATV/r (Stage 1: TDF 300 mg QD+ATV/r 300/100 mg QD+DTG 50 mg QD)	psnakpgfct(puokhytrrd) = aweonbltjb dijtpojwlx (amyblamiul, hiiuirgpte - nwnerwynpg) View more
NCT01803074 (AI468002, Pubmed \| Clin Infect Dis)	Phase 2	HIV Infections	107	GSK3532795	nznrnwgzsd(enaapysqhf) = gpcqzmrhcx zavmoyefba (orvfrlrvgk )	-	01 Aug 2017
AI468038 (205891) (IAS2017)	Not Applicable	HIV Infections	210	GSK3532795 60 mg + TDF/FTC QD	mfprpsntdd(pdrkhtzwrm) = jmrsikmczx kuaxyykuia (qilugmshpy ) View more	-	01 Jan 2017
				GSK3532795 120 mg + TDF/FTC QD	mfprpsntdd(pdrkhtzwrm) = qiihzjzqkk kuaxyykuia (qilugmshpy ) View more
IAS2015	Not Applicable	HIV Infections	-	BMS-955176	stljfzwndr(qvutmbyjea) = lsmamugcsc kflyvozycm (btjjukljiw, 3.4) View more	-	01 Jan 2015