Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists

Chiba, Jun; Takayama, Gensuke; Takashi, Tohru; Yokoyama, Mika; Nakayama, Atsushi; Baldwin, John J.; McDonald, Edward; Moriarty, K.J.M.; Sarko, Christopher R.; Saionz, Kurt W.; Swanson, R. N.; Hussain, Zahid; Wong, Angela; Machinaga, Nobuo

doi:10.1016/j.bmc.2005.11.058

Cited by 32 publications

(29 citation statements)

References 28 publications

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“…61 Finally, Chiba and coworkers synthesized very late antigen-4 (VLA-4) antagonists containing a clp or Clp residue. 62 To the best of our knowledge, the effects of 4-chloro substitution on proline ring pucker and peptide-bond isomerization have not been described previously. Likewise, neither clp nor Clp have been incorporated in CRPs or other acyclic peptides.…”

Section: Introductionmentioning

confidence: 92%

“…Boc-Hyp-OBn (1) and Boc-hyp-OBn (2) prepared as we described previously 63 were converted to Boc-clp-OBn (3) and Boc-Clp-OBn (4) via an Appel reaction, 64 which had been used previously for the synthesis of 4-chloroproline derivatives. 62,65 Subsequent hydrogenolysis of the benzyl group and then exchange of the N-Boc protecting group for an N-Fmoc protecting group afforded Fmoc-clp-OH (7) and Fmoc-Clp-OH (8).…”

Section: Synthesis Of 4-chloroproline Residuesmentioning

confidence: 99%

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4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

2007

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Collagen is an abundant, triple-helical protein comprising three strands of the repeating sequence: Xaa-Yaa-Gly. (2S)-Proline and (2S,4R)-4-hydroxyproline (Hyp) are common in the primary structure of collagen. Here, we use nonnatural proline derivatives to reveal determinants of collagen stability. Specifically, we report high-yielding syntheses of (2S,4S)-4-chloroproline (clp) and (2S, 4R)-4-chloroproline (Clp). We find that the crystal structure of Ac-Clp-OMe is virtually identical to that of Ac-Hyp-OMe. In contrast, the conformational properties of Ac-clp-OMe are similar to those of Ac-Pro-OMe. Ac-Clp-OMe has a stronger preference for a trans amide bond than does Ac-ProOMe, whereas Ac-clp-OMe has a weaker preference. (Pro-Clp-Gly) 10 forms triple helices that are significantly more stable than those of (Pro-Pro-Gly) 10 . Triple helices of (clp-Pro-Gly) 10 have stability similar to those of (Pro-Pro-Gly) 10 . Unlike (Pro-Clp-Gly) 10 and (clp-Pro-Gly) 10 , (clpClp-Gly) 10 does not form a stable triple helix, presumably due to a deleterious steric interaction between proximal chlorines on different strands. These data, which are consistent with previous work on 4-fluoroprolines and 4-methylprolines, support the importance of stereoelectronic and steric effects in the stability of the collagen triple helix and provide another means to modulate that stability.

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Section: Introductionmentioning

confidence: 92%

Section: Synthesis Of 4-chloroproline Residuesmentioning

confidence: 99%

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

2007

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“…1). 23) Next, appending a variety of substituents into pyrrolidine ring and benzene ring of benzoic acid portion of 6 was focused on.…”

Section: -(Pyrrolidinyl)methoxybenzoic Acid Derivatives As a Potentmentioning

confidence: 99%

“…Pyrrolidine derivatives 8a-c, 8e, 11a-n, and 14a-g were prepared from L-proline derivatives 17, 22, and 26 23,25) as shown in Chart 2-6.…”

Section: Chemistrymentioning

confidence: 99%

“…As a result of this study, 3-hydroxyprolyl-1-piperazinylacetic acid 2 (IC 50 ϭ1.1 nM) and 3,4-dihydroxyprolyl-1-piperazinylacetic acid 3 (IC 50 ϭ1.4 nM) were identified; both these compounds have moderate plasma clearance (2, 30 ml/min/kg; 3, 21 ml/min/kg) in rats. 23) We also have made it clear that the improvement of plasma clearance is caused by the change of the main excretion pathway, from bile for 1 to urine for 2 and 3. 12) Unfortunately, neither 2 nor 3 showed any oral availability.…”

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confidence: 99%

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4-(Pyrrolidinyl)methoxybenzoic Acid Derivatives as a Potent, Orally Active VLA-4 Antagonist

Chiba

Iimura

Yoneda

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC 50 ‫6.1؍‬ nM each) and moderate lipophilicity (Log D‫,0.2؍‬ 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.

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Conformational preferences of 4‐chloroproline residues

Park¹,

Byun²,

Motooka³

et al. 2012

Biopolymers

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Conformational preferences of the (2S,4R)-4-chloroproline (Clp) and (2S,4S)-4-chloroproline (clp) residues are explored at the M06-2X/cc-pVTZ//M06-2X/6-31+G(d) level of theory in the gas phase and in water, where solvation free energies were calculated using the implicit solvation model, and by an X-ray diffraction study in the solid state. In the gas phase, the down-puckered γ-turn structure with the trans prolyl peptide bond is most preferred for both Ac-Clp-NHMe and Ac-clp-NHMe, in which the C(7) hydrogen bond between two terminal groups seems to play a role, as found for Ac-Pro-NHMe. In water, the Clp residue has a strong preference for the up-puckered PP(II) structure, whereas the up-puckered PP(II) structure prevails a little over the down-puckered PP(II) structure for the clp residue, similar to the Pro residue. Hence, our calculated results on the puckering preference of the Clp and clp residues in water are in accord with the observed results deduced from the relative stabilities of the triple helices of the collagen model peptides. The X-ray structure of Ac-clp-NHMe was found to be the most preferred in water but that of Ac-Clp-NHMe was located as a local minimum with ΔG = 2.0 kcal/mol. In particular, the X-ray structure of Ac-Clp-NHMe was quite different from that of Ac-Clp-OMe but similar to that of Ac-Pro-NHMe. The lowest rotational barriers to the prolyl cis-trans isomerization for Ac-Clp-NHMe become nearly the same as those for Ac-Pro-NHMe in water, whereas the barriers are lower by ∼2 kcal/mol for Ac-clp-NHMe. It was found that the cis-trans isomerization may proceed through the clockwise or anticlockwise rotations for Ac-Clp-NHMe and the anticlockwise rotation for Ac-clp-NHMe and Ac-Pro-NHMe in water.

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Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists

Cited by 32 publications

References 28 publications

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

4-(Pyrrolidinyl)methoxybenzoic Acid Derivatives as a Potent, Orally Active VLA-4 Antagonist

Conformational preferences of 4‐chloroproline residues

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