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Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies.
J Med Chem. 1998 Apr 23; 41(9):1446-55.JM

Abstract

Comparison of the high-resolution X-ray structures of the native HIV-1 protease and its complexes with the inhibitors suggested that the enzyme flaps are flexible. The movement at the tip of the flaps could be as large as 7 A. On the basis of this observation, cyclic cyanoguanidines have been designed, synthesized, and evaluated as HIV-1 protease (PR) inhibitors. Cyclic cyanoguanidines were found to be very potent inhibitors of HIV-1 protease. The choice of cyclic cyanoguanidines over cyclic guanidines was based on the reduced basicity of the former. X-ray structure studies of the HIV PR complex with cyclic cyanoguanidine demonstrated that in analogy to cyclic urea, cyclic cyanoguanidines also displace the unique structural water molecule. The structure-activity relationship of the cyclic cyanoguanidines is compared with that of the corresponding cyclic urea analogues. The differences in binding constants of the two series of compounds have been rationalized using high-resolution X-ray structure information.

Authors+Show Affiliations

Jadhav PK
Chemical and Physical Sciences Department, The DuPont Merck Pharmaceutical Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. Prabhakar.K.Jadhav@dupontmerck.com
Woerner FJ
No affiliation info available
Lam PY
No affiliation info available
Hodge CN
No affiliation info available
Eyermann CJ
No affiliation info available
Man HW
No affiliation info available
Daneker WF
No affiliation info available
Bacheler LT
No affiliation info available
Rayner MM
No affiliation info available
Meek JL
No affiliation info available
Erickson-Viitanen S
No affiliation info available
Jackson DA
No affiliation info available
Calabrese JC
No affiliation info available
Schadt M
No affiliation info available
Chang CH
No affiliation info available

MeSH

Anti-HIV AgentsCell LineCrystallography, X-RayGuanidinesHIV ProteaseHIV Protease InhibitorsHIV-1HumansHydrogen BondingModels, MolecularStructure-Activity RelationshipUrea

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

9554878

Citation

Jadhav, P K., et al. "Nonpeptide Cyclic Cyanoguanidines as HIV-1 Protease Inhibitors: Synthesis, Structure-activity Relationships, and X-ray Crystal Structure Studies." Journal of Medicinal Chemistry, vol. 41, no. 9, 1998, pp. 1446-55.
Jadhav PK, Woerner FJ, Lam PY, et al. Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies. J Med Chem. 1998;41(9):1446-55.
Jadhav, P. K., Woerner, F. J., Lam, P. Y., Hodge, C. N., Eyermann, C. J., Man, H. W., Daneker, W. F., Bacheler, L. T., Rayner, M. M., Meek, J. L., Erickson-Viitanen, S., Jackson, D. A., Calabrese, J. C., Schadt, M., & Chang, C. H. (1998). Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies. Journal of Medicinal Chemistry, 41(9), 1446-55.
Jadhav PK, et al. Nonpeptide Cyclic Cyanoguanidines as HIV-1 Protease Inhibitors: Synthesis, Structure-activity Relationships, and X-ray Crystal Structure Studies. J Med Chem. 1998 Apr 23;41(9):1446-55. PubMed PMID: 9554878.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies. AU - Jadhav,P K, AU - Woerner,F J, AU - Lam,P Y, AU - Hodge,C N, AU - Eyermann,C J, AU - Man,H W, AU - Daneker,W F, AU - Bacheler,L T, AU - Rayner,M M, AU - Meek,J L, AU - Erickson-Viitanen,S, AU - Jackson,D A, AU - Calabrese,J C, AU - Schadt,M, AU - Chang,C H, PY - 1998/5/23/pubmed PY - 1998/5/23/medline PY - 1998/5/23/entrez SP - 1446 EP - 55 JF - Journal of medicinal chemistry JO - J Med Chem VL - 41 IS - 9 N2 - Comparison of the high-resolution X-ray structures of the native HIV-1 protease and its complexes with the inhibitors suggested that the enzyme flaps are flexible. The movement at the tip of the flaps could be as large as 7 A. On the basis of this observation, cyclic cyanoguanidines have been designed, synthesized, and evaluated as HIV-1 protease (PR) inhibitors. Cyclic cyanoguanidines were found to be very potent inhibitors of HIV-1 protease. The choice of cyclic cyanoguanidines over cyclic guanidines was based on the reduced basicity of the former. X-ray structure studies of the HIV PR complex with cyclic cyanoguanidine demonstrated that in analogy to cyclic urea, cyclic cyanoguanidines also displace the unique structural water molecule. The structure-activity relationship of the cyclic cyanoguanidines is compared with that of the corresponding cyclic urea analogues. The differences in binding constants of the two series of compounds have been rationalized using high-resolution X-ray structure information. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9554878/Nonpeptide_cyclic_cyanoguanidines_as_HIV_1_protease_inhibitors:_synthesis_structure_activity_relationships_and_X_ray_crystal_structure_studies_ L2 - https://doi.org/10.1021/jm970524i DB - PRIME DP - Unbound Medicine ER -