Literature DB >> 24900235

Discovery of INCB9471, a Potent, Selective, and Orally Bioavailable CCR5 Antagonist with Potent Anti-HIV-1 Activity.

Chu-Biao Xue1, Lihua Chen1, Ganfeng Cao1, Ke Zhang1, Anlai Wang1, David Meloni1, Joseph Glenn1, Rajan Anand1, Michael Xia1, Ling Kong1, Taisheng Huang1, Hao Feng1, Changsheng Zheng1, Mei Li1, Laurine Galya1, Jiacheng Zhou1, Niu Shin1, Fredric Baribaud1, Kim Solomon1, Peggy Scherle1, Bitao Zhao1, Sharon Diamond1, Tom Emm1, Douglas Keller1, Nancy Contel1, Swamy Yeleswaram1, Kris Vaddi1, Gregory Hollis1, Robert Newton1, Steven Friedman1, Brian Metcalf1.   

Abstract

To identify a CCR5 antagonist as an HIV-1 entry inhibitor, we designed a novel series of indane derivatives based on conformational considerations. Modification on the indane ring led to the discovery of compound 22a (INCB9471) that exhibited high affinity for CCR5, potent anti-HIV-1 activity, high receptor selectivity, excellent oral bioavailability, and a tolerated safety profile. INCB9471 has entered human clinical trials.

Entities:  

Keywords:  CCR5; HIV-1; antagonist; antiviral; coreceptor

Year:  2010        PMID： 24900235      PMCID： PMC4007949          DOI： 10.1021/ml1001536

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  15 in total

Review 1.  The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS.

Authors:  Anthony Wood; Duncan Armour
Journal:  Prog Med Chem       Date:  2005

Review 2.  Discovery and development of small-molecule chemokine coreceptor CCR5 antagonists.

Authors:  Anandan Palani; Jayaram R Tagat
Journal:  J Med Chem       Date:  2006-05-18       Impact factor: 7.446

3.  Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety.

Authors:  M Shiraishi; Y Aramaki; M Seto; H Imoto; Y Nishikawa; N Kanzaki; M Okamoto; H Sawada; O Nishimura; M Baba; M Fujino
Journal:  J Med Chem       Date:  2000-05-18       Impact factor: 7.446

4.  Identification of a major co-receptor for primary isolates of HIV-1.

Authors:  H Deng; R Liu; W Ellmeier; S Choe; D Unutmaz; M Burkhart; P Di Marzio; S Marmon; R E Sutton; C M Hill; C B Davis; S C Peiper; T J Schall; D R Littman; N R Landau
Journal:  Nature       Date:  1996-06-20       Impact factor: 49.962

5.  HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5.

Authors:  T Dragic; V Litwin; G P Allaway; S R Martin; Y Huang; K A Nagashima; C Cayanan; P J Maddon; R A Koup; J P Moore; W A Paxton
Journal:  Nature       Date:  1996-06-20       Impact factor: 49.962

6.  CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1.

Authors:  G Alkhatib; C Combadiere; C C Broder; Y Feng; P E Kennedy; P M Murphy; E A Berger
Journal:  Science       Date:  1996-06-28       Impact factor: 47.728

7.  The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression.

Authors:  N L Michael; G Chang; L G Louie; J R Mascola; D Dondero; D L Birx; H W Sheppard
Journal:  Nat Med       Date:  1997-03       Impact factor: 53.440

8.  Inhibition of the development of collagen-induced arthritis in rhesus monkeys by a small molecular weight antagonist of CCR5.

Authors:  Michel P M Vierboom; Paul J Zavodny; Chuan-Chu Chou; Jayaram R Tagat; Catherine Pugliese-Sivo; Julie Strizki; Ruo W Steensma; Stuart W McCombie; Liesbeth Celebi-Paul; Ed Remarque; Margreet Jonker; Satwant K Narula; Bert't Hart
Journal:  Arthritis Rheum       Date:  2005-02

9.  Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist.

Authors:  Jayaram R Tagat; Stuart W McCombie; Dennis Nazareno; Marc A Labroli; Yushi Xiao; Ruo W Steensma; Julie M Strizki; Bahige M Baroudy; Kathleen Cox; Jean Lachowicz; Geoffrey Varty; Robert Watkins
Journal:  J Med Chem       Date:  2004-05-06       Impact factor: 7.446

Review 10.  Targeting of Th1-associated chemokine receptors CXCR3 and CCR5 as therapeutic strategy for inflammatory diseases.

Authors:  J E Turner; O M Steinmetz; R A Stahl; U Panzer
Journal:  Mini Rev Med Chem       Date:  2007-11       Impact factor: 3.862
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  4 in total

Review 1.  CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV.

Authors:  Michelle B Kim; Kyle E Giesler; Yesim A Tahirovic; Valarie M Truax; Dennis C Liotta; Lawrence J Wilson
Journal:  Expert Opin Investig Drugs       Date:  2016-12       Impact factor: 6.206

2.  Discovery of Novel CCR5 Ligands as Anticolorectal Cancer Agents by Sequential Virtual Screening.

Authors:  Mariam A El-Zohairy; Darius P Zlotos; Martin R Berger; Hassan H Adwan; Yasmine M Mandour
Journal:  ACS Omega       Date:  2021-04-16

Review 3.  HIV-1 Entry and Prospects for Protecting against Infection.

Authors:  Jean-François Bruxelle; Nino Trattnig; Marianne W Mureithi; Elise Landais; Ralph Pantophlet
Journal:  Microorganisms       Date:  2021-01-22

Review 4.  Medicinal chemistry strategies toward host targeting antiviral agents.

Authors:  Xingyue Ji; Zhuorong Li
Journal:  Med Res Rev       Date:  2020-02-14       Impact factor: 12.944
  4 in total

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