Optimization of the aminopyridopyrazinones class of PDE5 inhibitors: Discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 17, 2009, Pages 5209-5213

  Hughes, Robert O ^a   Walker, John K ^a   Joseph Rogier, D ^a   Heasley, Steve E ^a   Blevis Bal, Rhadika M ^a   Benson, Alan G ^a   Jon Jacobsen, E ^a   Cubbage, Jerry W ^a   Fobian, Yvette M ^a   Owen, Dafydd R ^b   Freskos, John N ^a   Molyneaux, John M ^a   Brown, David L ^a   Acker, Brad A ^a   Maddux, Todd M ^a   Tollefson, Mike B ^a   Moon, Joseph B ^a   Mischke, Brent V ^a   Rumsey, Jeanne M ^a   Zheng, Yi ^a   MacInnes, Alan ^a   Bond, Brian R ^a   Yu, Ying ^a   more..

^a PFIZER INC   (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Aminopyrazinone; PDE5; Pharmacokinetics

Indexed keywords

3 [(4 HYDROXYCYCLOHEXYL)AMINO] 7 (6 METHOXYPYRIDIN 3 YL) 1 (2 PROPOXYETHYL)PYRIDO[3,4 B]PYRAZIN 2(1H) ONE; PHOSPHODIESTERASE V; PHOSPHODIESTERASE V INHIBITOR; PHOSPHODIESTERASE VI; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIHYPERTENSIVE ACTIVITY; ARTICLE; CONTROLLED STUDY; DOG; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; IC 50; NONHUMAN; RAT; SPECIES DIFFERENCE; SPONTANEOUSLY HYPERTENSIVE RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 5; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 6; DOGS; DRUG DISCOVERY; HUMANS; PHOSPHODIESTERASE 5 INHIBITORS; PHOSPHODIESTERASE INHIBITORS; PROTEIN ISOFORMS; PYRAZINES; PYRIDINES; RATS; RATS, INBRED SHR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 68349137668     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.019     Document Type: Article

References (17)

1. See for instance:. Wolk R., Smith W.B., Neutal J.M., Rubino J., Xuan D., Mancuso J., Gilbert J., and Pressler M.L. Hypertension 53 (2009) 1091
2. Owen D.R., Walker J.K., Jacobsen E.J., Freskos J.N., Hughes R.O., Brown D.L., Bell A.S., Brown D.G., Phillips C., Mischke B.V., Molyneaux J.M., Fobian Y.F., Heasley S.E., Moon J.B., Stallings W.C., Rogier D.J., Fox D.A., Plamer M.J., Ringer T., Rodriquez-Lens M., Cubbage J.W., Blevis R.M., Benson A.G., Acker B.A., Maddux T.M., Tollefson M.B., Bond B.R., MacInnes A., and Yu Y. Bioorg. Med. Chem. Lett. 19 (2009) 4088
3. Hughes R.O., Walker J.K., Cubbage J.W., Fobian Y.M., Rogier D.J., Heasley S.E., Blevis-Bal R.M., Benson A.G., Owen D.R., Jacobsen E.J., Freskos J.N., Molyneaux J.M., Brown D.L., Stallings W.C., Acker B.A., Maddux T.M., Tollefson M.B., Williams J.M., Moon J.B., Mischke B.V., Rumsey J.M., Zheng Y., MacInnes A., and Bond B.R. Bioorg. Med. Chem. Lett. 19 (2009) 4092
4. 1/2 (in rat) of 3-4 h would likely translate into a once-a-day profile in man:. Hosea N.A., Collard W.T., Cole S., Maurer T.S., Fang R.X., Jones H., Kaker S.M., Nakai Y., Smith B.J., Webster R., and Beaumont K. J. Clin. Pharm. 49 (2009) 513
5. Van de Waterbeemd H., Smith D.A., and Jones B.C. J. Comput. Aided Mol. Des. 15 (2001) 239
6. 50 >2000 nM (>28,000-fold).
7. 50.
8. This is a general trend. Over a larger set of compounds than is shown in Table 1 the southeastern isomers is approximately 6-times more potent than the southern isomer; Over the same set of compounds the southern isomer is roughly threefold less potent against PDE6.
9. The Pfizer Institutional Animal Care and Use Committee reviewed and approved the animal use in these studies. The animal care and use program is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International.
10. See Ref. 3 for details of the SHR study.
11. Select compounds were found to be equipotent on rat and human versions of PDE5.
12. Additional metabolism resulted in cleavage of the propoxy group from the ethylpropoxy side chain and the methoxy group from the methoxy pyridyl moiety. The resultant compounds lost significant potency against PDE5 and PDE6.
13. Van de Waterbeemd H., Smith D.A., Beaumont K., and Walker D.K. J. Med. Chem. 44 (2001) 1313
14. Compound 14 → 41: 97-fold → 174-fold PDE6 selectivity; 15 → 42: 30-fold → 53-fold PDE6 selectivity.
15. Calculated utilizing the parameters determined from the rat PK experiments and ppb.
16. 50 >2000 nM (>41,000-fold).
17. -6 cm/s) and was determined not to be a PGP substrate.