N-Benzoyl amino acids as LFA-1/ICAM inhibitors 1: amino acid structure–activity relationship

Burdick, Daniel J.; Paris, K.; Weese, Kenneth J.; Stanley, Mark; Beresini, Maureen H.; McDowell, Robert S.; Marsters, James C.; Gadek, Thomas R.

doi:10.1016/s0960-894x(03)00084-2

Cited by 18 publications

(15 citation statements)

References 13 publications

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“…Scientific publications detail the discovery of this series of LFA-1 antagonists by Genentech [176,215,216]; similar structures have also been disclosed in patents from Hoffmann-La Roche [217,218] and a patent application by Celltech [219]. Compound (46) demonstrated inhibition of the LFA-1/ICAM function in a molecular assay with an IC 50 = 1.7 µM.…”

Section: N-benzoyl Amino Acid Based Antagonistsmentioning

confidence: 83%

“…An amino acid scan to investigate the importance of the tryptophan moiety revealed it to be one of the preferred amino acids [216]. Structural activity studies of the Nbenzoyl moiety identified antagonist (48) which exhibited a significant increase in binding affinity (LFA-1/ICAM IC 50 = 47 nM) and was active in the MLR assay (IC 50 = 10.3 µM) [176].…”

Section: N-benzoyl Amino Acid Based Antagonistsmentioning

confidence: 99%

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LFA-1 as a Key Regulator of Immune Function: Approaches toward the Development of LFA-1-Based Therapeutics

Rm²

2006

CPD

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Over the past decade, Lymphocyte Function-Associated Antigen-1 (LFA-1, alphaLbeta2, CD11a/CD18) has emerged as an attractive therapeutic target for the treatment of multiple inflammatory diseases. Its established role in the trafficking and activation of leukocytes coupled with the recent elucidation of the global conformational changes that govern its function continue to drive pharmaceutical interest in this target. This sustained interest has led to the implementation of numerous drug discovery strategies leading to the development of antibodies, peptidomimetics, and small molecules that block LFA-1 function. The most successful demonstration of clinical efficacy to date has been with Raptiva, a humanized anti-LFA-1 antibody. In clinical trials of patients with moderate to severe psoriasis, improvements in several disease specific parameters including the Psoriasis Area and Severity Index (PASI) were observed. This review article will provide an overview of LFA-1 biology and structural regulation, as well as strategies that have been adopted in pursuit of effective therapies. Recent findings with different classes of small molecule antagonists will be highlighted with an emphasis on how their different mechanisms of action on the inserted domain (I domain) of CD11a have impacted our understanding of LFA-1 function and illuminated other potential avenues for therapeutic intervention.

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Section: N-benzoyl Amino Acid Based Antagonistsmentioning

confidence: 83%

Section: N-benzoyl Amino Acid Based Antagonistsmentioning

confidence: 99%

LFA-1 as a Key Regulator of Immune Function: Approaches toward the Development of LFA-1-Based Therapeutics

Rm²

2006

CPD

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“…8 Combining the results of this work with the current benzoyl SAR evaluation, we were able to produce compounds with further enhanced potency. These results are displayed in Table 4.…”

mentioning

confidence: 76%

“…This influence on potency appears to be a combination of steric and electronic effects. For example, the medium sized hydroxy (8) and methoxy substitutions are approximately 300-and 100-fold, respectively, less potent than the bromo substitution (1) and they are approximately 4-and 2-fold, respectively, less potent than the un-substituted benzoyl ring (2) itself. The alkoxy groups stabilize the co-planarity of the ring and amide bond with a large electronic resonance effect, as well as, internal hydrogen bonding with the amide bond NH hydrogen.…”

mentioning

confidence: 99%

N -Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: Structure–activity relationship of the benzoyl moiety

Burdick¹,

Marsters²,

Aliagas-Martin³

et al. 2004

Bioorganic & Medicinal Chemistry Letters

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“…On the basis of experience previously acquired with the design of RGD (Arg-Gly-Asp) peptidomimetics, this approach yielded a cyclic peptide lead to an LFA-1 antagonist with micromolar IC 50 values The pharmacophoric points of this peptide were subsequently mimicked on an N-benzoyl-substituted tryptophan scaffold and optimized using a modular approach (Burdick et al 2003(Burdick et al , 2004. This class of LFA-1 antagonists compete with nanomolar affinity with ICAM-1 for a common binding site in the I-domain of the alpha subunit of LFA-1 (Keating et al 2006) and are mechanistically distinct from allosteric LFA-1 antagonists discovered by other organizations (Liu et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug

Khojasteh¹,

Leipold²,

Lai

et al. 2008

Xenobiotica

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1) Intercellular adhesion molecule (ICAM)-1988 is a small molecule lymphocyte functionassociated antigen-1 (LFA-1) antagonist being considered for its anti-inflammatory properties. Following intravenous administration of ICAM1988, clearances in mice, rats, dogs, and monkeys were 17.8, 3.31, 15.4, and 6.85 ml min À1 kg À1 , respectively.(2) In mass balance studies using [ 14 C]-ICAM1988 in rats dosed intravenously, unchanged ICAM1988 contributed to 25.1% of the dose. (3) In rats, the systemic bioavailability of ICAM1988 was improved to 0.28 when the drug was administered orally as its isobutyl ester, ICAM2660. In rats, this was consistent with the complete in vitro conversion of ICAM2660 to ICAM1988 in plasma, and liver and intestinal S9. (4) In dogs and monkeys, ICAM2660 did not improve the bioavailability of ICAM1988. This is consistent with limited in vitro conversion of ICAM2660 to ICAM1988 in plasma and liver S9. (5) In human in vitro studies, ICAM2660 conversion to ICAM1988 in liver was similar to rats while no conversion in plasma and intestinal S9 fractions were observed. Based on the in vitro metabolism similarities of human and rat, it would be anticipated that in human oral administration of ICAM2660 would improve the systemic exposure of ICAM1988.

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N-Benzoyl amino acids as LFA-1/ICAM inhibitors 1: amino acid structure–activity relationship

Cited by 18 publications

References 13 publications

LFA-1 as a Key Regulator of Immune Function: Approaches toward the Development of LFA-1-Based Therapeutics

LFA-1 as a Key Regulator of Immune Function: Approaches toward the Development of LFA-1-Based Therapeutics

N -Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: Structure–activity relationship of the benzoyl moiety

Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug

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